Escitalopram (Systemic)


VA CLASSIFICATION
Primary: CN603

Commonly used brand name(s): Lexapro.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antidepressant —

Indications

Accepted

Depressive disorder, major (treatment)—Escitalopram is indicated for the treatment of major depressive disorder. In an 8-week controlled trial, outpatients given a 10 mg per day or 20 mg per day dose showed significantly greater mean improvement compared to placebo on the Montgomery Asberg Depression Rating Scale (MADRS). Longer-term efficacy of escitalopram in major depressive disorder has not been systematically evaluated. {01}

Note: The efficacy of escitalopram in the treatment of major depressive disorder was established, in part, on the basis of extrapolation from the established effectiveness of racemic citalopram, of which escitalopram is the active isomer.{01}



Pharmacology/Pharmacokinetics

Escitalopram is an enantiomer of citalopram, for pharmacology and pharmacokinetic information on citalopram refer to Pharmacology and Pharmacokinetics, Citalopram (Systemic).

Physicochemical characteristics:
Source—
    Escitalopram is a pure S-enantiomer of the racemic, bicyclic phthalane derivative citalopram. {01}
Molecular weight—
    414.40 {01}

Solubility
    Escitalopram is freely soluble in methanol and dimethylsulfoxide (DMSO), sparingly soluble in water and in ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.{01}

Mechanism of action/Effect:

Escitalopram is a selective serotonin reuptake inhibitor (SSRI). The mechanism of antidepressant action of escitalopram is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from its inhibition of central nervous system neuronal reuptake of serotonin (5-HT). It is a highly selective SSRI with minimal effects on norephinephrine and dopamine neuronal reuptake. {01}

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-HT1-7) or other receptors including alpha- and beta- adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5) and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K +, Cl- and Ca ++ channels. {01}

Absorption:

Escitalopram absorption is not affected by food. {01}

In elderly patients the area under the concentration curve (AUC) is increased by 50%.{01}

Protein binding:

Moderate (approximately 56%) to plasma protein {01}

Biotransformation:

Escitalopram is mainly metabolized via hepatic pathways to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). 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 using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.{01}

Half-life:

Approximately 27 to 32 hours.{01}

In the elderly patients the half-life increased by approximately 50%.{01}

Due to a doubling of half life with citalopram in hepatically impaired patients, escitalopram half life is expected to be greater also.{01}

Time to peak concentration:

Following a single oral dose (20 milligram tablet) the mean Tmax was 5 ± 1.5 hours.{01}

Elimination:
    Oral clearance of escitalopram is 600 milliliters per minute, with approximately 7% of that due to renal clearance.{01}
    Following oral administration, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram is approximately 8% and 10%, respectively. {01}
    Due to an oral clearance reduction of citalopram by 37% in patients with reduced hepatic function, escitalopram clearance can be anticipated to be reduced as well. Dosing adjustments are recommended.{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Escitalopram is contraindicated in patients known to be hypersensitive to citalopram, escitalopram or other components of the product.{01}

Carcinogenicity

There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg per kg of body weight per day for 18 months. However, there was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg per kg of body weight per day for 24 months. A no-effect dose for this finding was not established. {01}

Mutagenicity

Racemic citalopram was mutagenic in two of five bacterial strains (Salmonella TA98 and TA1537) in the in vitro bacterial reverse mutation assay in the absence of metabolic activations and 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 also not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays. {01}

Pregnancy/Reproduction
Fertility—
Studies in male and female rats given oral racemic citalopram doses ranging from 16 to 72 mg per kg of body weight per day found fertility to be decreased at doses greater than or equal to 32 mg per kg of body weight per day and mating was decreased at all doses. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. {01}

In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. {01}

In a rat embryo/fetal development study, oral administration of escitalopram to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at doses approximately greater than or equal to 56 times the maximum recommended human dose [MRHD] of 20 mg per day on a mg/m 2 basis. Maternal toxicity was present at all dose levels and mild at 56 mg per kg of body weight per day. The developmental no effect dose of 56 mg per kg of body weight per day is approximately 28 times the MRHD on a mg/m 2 basis. No teratogenicity was observed at any of the doses tested as high as 75 times the MRHD on a mg/m 2 basis. {01} In two rat embryo/fetal development studies, oral administration of racemic citalopram to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival, an increased incidence of fetal abnormalities including cardiovascular and skeletal defects, and maternal toxicity at the high dose of 112 mg per kg of body weight per day. The developmental no effect dose was 56 mg per kg of body weight per day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg per kg of body weight per day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. {01}

Administration of escitalopram to female rats during pregnancy and through weaning at oral doses ranging from 6 to 48 mg per kg of body weight resulted in a slightly increased offspring mortality, growth retardation, and maternal toxicity at 48 mg per kg of body weight per day which is approximately 24 times the MRHD on a mg/m 2basis. Slightly increased offspring mortality was seen at 24 mg per kg of body weight per day. The no effect dose was 12 mg per kg of body weight per day which is approximately 6 times the MRHD on a mg/m 2basis. {01} Administration of racemic citalopram to female rats from late gestation through weaning at oral doses ranging from 4.8 to 32 mg per kg of body weight per day resulted in increased offspring mortality during the first four days after birth and persistent offspring growth retardation at the highest dose. The no effect dose was 12.8 mg per kg of body weight per day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses greater than or equal to 24 mg per kg of body weight per day. A no effect dose was not determined in that study. {01} Administration of racemic citalopram to male and female rats at oral doses ranging from 16 to 72 mg per kg of body weight per day resulted in an increase in gestation duration at 48 mg per kg of body weight per day.{01}

FDA Pregnancy Category C {01}


Labor and delivery—

The effect of escitalopram on labor and delivery in humans is unknown {01}

Breast-feeding

Racemic citalopram is distributed into human breast milk. Excessive somnolence, decreased feeding, and weight loss have been reported in association with breast feeding from a citalopram-treated mother. In one case, the infant was reported to recover completely upon discontinuation of citalopram by the mother. The second case provided no available follow up information. The decision whether to continue or discontinue either nursing or escitalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of treatment for the mother. {01}

Pediatrics

No information is available on the relationships of age to the effects of escitalopram in pediatric patients. Safety and efficacy have not been established. {01}


Geriatrics


Escitalopram AUC and half life were increased approximately 50% in elderly subjects ³ 65 years of age as compared to younger subjects in clinical studies; decreased dosing is recommended for elderly patients.{01}

The number of elderly patients 60 years of age or older who received escitalopram in controlled trials was insufficient to assess differences in safety and efficacy on the basis of age. In clinical studies of racemic citalopram, no overall differences in safety or effectiveness were observed between elderly patients and younger patients. However, greater sensitivity of some elderly individuals to effects of escitalopram cannot be ruled out. {01}


Pharmacogenetics

In a multiple-dose study of escitalopram, there were no differences based on gender in AUC, C max, and half life. No adjustment of dosage on the basis of gender is needed. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol    (although studies indicate that racemic citalopram did not increase the cognitive and motor effects of alcohol, concurrent use is not recommended {01})


CYP2D6 metabolized drugs such as:
tricyclic antidepressants     (in vivo studies suggest a modest CYP2D6 inhibitory effect for escitalopram; coadministration of escitalopram with the tricyclic antidepressant desipramine, a substrate for CYP2D6, resulted in increases of Cmax and AUC of desipramine by 40% and 100%, respectively; caution is recommended in concurrent use of escitalopram and drugs metabolized by CYP2D6 {01})


Carbamazepine    (due to the enzyme inducing properties of carbamazepine, a CYP3A4 substrate, the possibility that carbamazepine might increase the clearance of escitalopram should be considered with concurrent use {01})


Central nervous system (CNS) drugs    (caution should be used due to the primary CNS effects of escitalopram {01})


Cimetidine    (AUC and Cmax of citalopram were increased by 43% and 39%, respectively , by concomitant cimetidine use; clinical significance is unknown{01})


» Citalopram    (since escitalopram is the active isomer of racemic citalopram, the two should not be co-administered{01} )


Ketoconazole    (Cmax and AUC of ketoconazole were decreased by 21% and 10%, respectively , by concomitant racemic citalopram use {01})


Lithium    (because lithium may enhance the serotonergic effects of escitalopram, caution is recommended and plasma lithium levels should be monitored and adjusted {01})


Metoprolol    (Cmax and AUC of metoprolol were increased by 50% and 82%, respectively, by concomitant escitalopram use; increased metoprolol plasma levels have been associated with decreased cardioselectivity, but no clinically significant effects on blood pressure or heart rate.{01})


» Monoamine oxidase inhibitors (MAOI's)    (Concomitant use is contraindicated. Serious and sometimes fatal reactions have occurred in patients receiving an SSRI with an MAOI; reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes including extreme agitation progressing to delirium and coma; some cases presented with features resembling neuroleptic malignant syndrome; these reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on an MAOI; concurrent use of an MAOI and escitalopram is contraindicated; at least 14 days should be allowed between discontinuation of one drug, escitalopram or MAOI, and the initiation of the other {01})


» Sumatriptan    (there have been rare postmarketing reports of patients with weakness, hyperreflexia and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) such as escitalopram and sumatriptan; appropriate observation of the patient is advised when concomitant treatment is clinically warranted {01})


Warfarin    (racemic citalopram did not affect the pharmacokinetics of warfarin; however, prothrombin time was increased by 5%, the clinical significance is unknown.{01})


Note: In vitro studies indicate that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of ritonavir, a potent inhibitor of CYP3A4, with escitalopram 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. {01}


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Altered metabolism or hemodynamic responses    (caution should be used in patients with diseases or conditions that produce altered metabolism or hemodynamic responses {01})


Drug abuse, history of    (patients with a history of drug abuse should be closely observed for signs of misuse or abuse such as development of tolerance, increased dose, and/or drug seeking behavior {01})


» Hepatic impairment    (racemic citalopram clearance was decreased and plasma concentrations were increased; recommended dose of escitalopram in hepatically impaired patients is 10 mg per day {01})


» Mania or hypomania, history of    (condition may be activated by escitalopram; caution should be used in patients with history of mania or hypomania {01})


» Renal impairment, severe    (until adequate numbers of patients with severe renal impairment (creatinine clearance < 20 mL per min) have been evaluated during chronic treatment with escitalopram, it should be used with caution {01})


» Seizure disorder, history of    (escitalopram should be introduced with caution in patients with a history of seizure disorder {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Close supervision of patients with suicidal tendencies    (recommended especially during initial escitalopram therapy; good patient management practices with prescriptions for the smallest quantity of tablets {01})


Reevaluation of the long-term usefulness of the drug    (periodic evaluations are recommended to assess the usefulness of escitalopram for the individual patient; the longer-term efficacy has not been systematically evaluated in controlled trials{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Hyponatremia (coma; confusion; convulsions; decreased urine output; dizziness; fast or irregular heartbeat; headache; increased thirst; muscle pain or cramps; nausea or vomiting; shortness of breath; swelling of face, ankles, or hands; unusual tiredness or weakness)— or syndrome of inappropriate antidiuretic hormone secretion{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abnormal ejaculation{01} (ejaculation delay)
    
constipation{01}
    
diarrhea{01}
    
dizziness{01}
    
dry mouth{01}
    
fatigue{01} (unusual tiredness or weakness)
    
impotence{01}
libido, decreased{01} (loss in sexual ability, desire, drive, or performance; decreased interest in sexual intercourse; inability to have or keep an erection)
    
increased sweating{01}
    
indigestion{01} (gas in stomach; heartburn; nausea; stomach pain)
    
insomnia{01} (sleeplessness; trouble sleeping; unable to sleep )
    
nausea{01}
    
somnolence{01} (sleepiness or unusual drowsiness)
{01}

Note: The incidence of constipation, diarrhea, dizziness, dry mouth, fatigue, increased sweating, indigestion, insomnia, and somnolence may be dose-related {01}.

Incidence less frequent
    
Abdominal pain{01}
    
anorgasmic{01} (not able to have an orgasm)
    
appetite, decreased{01}
    
influenza like symptoms{01} (chills; cough; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting )
    
rhinitis{01} ( stuffy nose; runny nose; sneezing)
    
sinusitis{01} (pain or tenderness around eyes and cheekbones; fever; stuffy or runny nose; headache; cough; shortness of breath or troubled breathing; tightness of chest or wheezing)



Occurrence upon discontinuation
Incidence less frequent
    
Abnormal ejaculation{01} (ejaculation delay)
    
nausea
{01}




Overdose
For specific information on the agents used in the management of escitalopram overdose, see Charcoal, Activated (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
There have been three reports of escitalopram overdose involving doses of up to 600 mg. All three patients recovered and no symptoms associated with the overdoses were reported. {01}

Note: Escitalopram effects of overdose were not reported. Because escitalopram is an racemic enantiomer of citalopram, the citalopram effects of overdose may be useful in evaluating escitalopram overdose. The following effects accompany citalopram overdose, alone or in combination with other drugs and/or alcohol: dizziness, sweating, nausea, vomiting, tremor, somnolence, sinus tachycardia, and convulsions. In more rare cases, observed symptoms include amnesia, confusion, coma, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and one possible case of Torsades de pointes.) {01}


Treatment of overdose
There are no specific antidotes for escitalopram. Treatment is essentially symptomatic and supportive. {01}


To decrease absorption:
Considering gastric evacuation by lavage and administration of activate charcoal {01}



Monitoring:
Cardiac and vital sign monitoring and careful observation are recommended{01}



Supportive care:
Establishing and maintaining an airway to ensure adequate ventilation and oxygenation {01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Note: Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. {01}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Escitalopram (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to escitalopram or citalopram

Pregnancy—Should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.





Breast-feeding—Racemic citalopram is distributed into human breast milk.





Use in the elderly—Elderly patients may have greater sensitivity to the effects of escitalopram; decreased dosing
Other medications, especially alcohol, citalopram, monoamine oxidase inhibitors (MAOI's) or sumatriptan
Other medical problems, especially hepatic impairment, history of mania or hypomania, history of seizure disorder, or severe renal impairment

Proper use of this medication
» Importance of continuing escitalopram even if improvement of symptoms is noticeable in the first 1 to 4 weeks

Proper dosing
Discussing with physician what to do about any missed doses

Proper storage

Precautions while using this medication
» Not taking escitalopram with or within 14 days of taking a monoamine oxidase inhibitor (MAOI), not taking an MAOI within 14 days of taking escitalopram

Avoiding use of alcoholic beverages

Possible impaired judgement, thinking or motor skills; not driving, operating machinery, or doing anything that could be dangerous until effects of medication are known


Side/adverse effects
Signs of potential side effects, especially hyponatremia or syndrome of inappropriate antidiuretic hormone secretion.


General Dosing Information
Patients who are at high risk for suicide attempts should be closely supervised and prescribed the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. {01}

Patients should be advised to continue escitalopram therapy as directed even though they may notice improvement of symptoms in one to four weeks. {01}

Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. {01}

At least 14 days should be allowed between discontinuation of escitalopram or monoamine oxidase inhibitors (MAOI's), and the initiation of the other. {01}

Diet/Nutrition
May be taken with or without food once daily in the morning or evening. {01}


Oral Dosage Forms

ESCITALOPRAM TABLETS

Usual adult dose
Antidepressant
Oral, initially 10 mg once daily. After a minimum of one week the dose may be increased to 20 mg once daily; however, a fixed dose trial of 10 mg and 20 mg doses of escitalopram failed to demonstrate a greater benefit of 20 mg over 10 mg.{01}

Note: For patients with hepatic impairment, the recommended dose is 10 mg once daily. For patients with mild or moderate renal impairment, no dosage adjustment is necessary. {01}



Usual pediatric dose
Antidepressant
Safety and efficacy have not been established {01}


Usual geriatric dose
Antidepressant
Oral, 10 mg once daily recommended for most elderly patients. {01}


Strength(s) usually available
U.S.—


5 mg (base) (Rx) [Lexapro ( croscarmellose sodium) (colloidal silicon dioxide ) (hydroxypropyl methyl cellulose) (magnesium stearate) (microcrystalline cellulose, ) (polyethylene glycol) (talc) (titanium dioxide){01}]


10 mg (base) (Rx) [Lexapro ( scored) (croscarmellose sodium) ( colloidal silicon dioxide) (hydroxypropyl methyl cellulose) (magnesium stearate) ( microcrystalline cellulose, ) (polyethylene glycol ) (talc) (titanium dioxide ){01}]


20 mg (base) (Rx) [Lexapro ( scored) (croscarmellose sodium) ( colloidal silicon dioxide) (hydroxypropyl methyl cellulose) (magnesium stearate) ( microcrystalline cellulose, ) (polyethylene glycol ) (talc) (titanium dioxide ){01}]

Canada—
Not commercially available.

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted between 15 and 30 °C (59 and 86 °F).{01}

Auxiliary labeling:
   • May impair judgement, thinking, or motor skills. Be careful while driving or operating machinery. Use caution until you become familiar with its effects.
   • Avoid alcoholic beverages



Developed: 01/21/2003



References
  1. Product Information: Lexapro™, escitalopram. Forest Pharmaceuticals, Inc., St. Louis, Missouri, (PI revised 08/2002) reviewed 11/2002.
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