Lexapro® (escitalopram) tablets
Lexapro® 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-[3(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5phthalancarbonitrile oxalate.
The molecular formula is C20H21FN2O•C2H2O4 and the molecular weight is 414.40.
Lexapro tablets are film-coated, round tablets containing 6.38 mg, 12.75 mg, 25.50 mg escitalopram oxalate in strengths equivalent to 5 mg, 10 mg, and 20 mg, respectively, of escitalopram base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: talc, croscarmellose sodium, microcrystalline cellulose/colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and polyethylene glycol.
Lexapro oral solution contains 1.29 mg/ml escitalopram oxalate equivalent to 1 mg/mL escitalopram base. It also contains the following inactive ingredients: sorbitol, purified water, citric acid, sodium citrate, malic acid, glycerin, propylene glycol, methylparaben, propylparaben, and natural peppermint flavor. The oral solution is not currently marketed.
INDICATIONS AND USAGE
Major Depressive Disorder
Lexapro (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
Lexapro 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.
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).
DOSAGE AND ADMINISTRATION
Lexapro should be administered once daily, in the morning or evening, with or without food.
Major Depressive Disorder
Adolescents: The recommended dose of Lexapro is 10 mg once daily. A flexible-dose trial of Lexapro (10 to 20 mg/day) demonstrated the effectiveness of Lexapro. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.
Adults: The recommended dose of Lexapro is 10 mg once daily. A fixed-dose trial of Lexapro demonstrated the effectiveness of both 10 mg and 20 mg of Lexapro, 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.
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 Lexapro 10 or 20 mg/day in adults’ patients with major depressive disorder who responded while taking Lexapro during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment. Nevertheless, the physician who elects to use Lexapro 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.
Generalized Anxiety Disorder
Adults: The recommended starting dose of Lexapro is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.
Generalized anxiety disorder is recognized as a chronic condition. The efficacy of Lexapro in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use Lexapro for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Screen for Bipolar Disorder Prior to Starting Lexapro
Prior to initiating treatment with Lexapro or another antidepressant, screen patients for a personal family history of bipolar disorder, mania, or hypomania.
Discontinuation of Treatment with Lexapro
Symptoms associated with discontinuation of Lexapro 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.
Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Lexapro. Conversely, at least 14 days should be allowed after stopping Lexapro before starting an MAOI intended to treat psychiatric disorders.
Use of Lexapro with Other MAOIs such as Linezolid or Methylene Blue
Do not start Lexapro 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.
Monoamine Oxidase Inhibitors (MAOIs): The use of MAOIs intended to treat psychiatric disorders with Lexapro or within 14 days of stopping treatment with Lexapro is contraindicated because of an increased risk of serotonin syndrome. The use of Lexapro within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
Starting Lexapro 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: Lexapro is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in Lexapro.
WARNINGS AND PRECAUTIONS
- SUICIDAL THOUGHTS AND BEHAVIORS: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Lexapro is not approved for use in pediatric patients less than 12 years of age
- Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including Lexapro, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue Lexapro and initiate supportive treatment. If concomitant use of Lexapro with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Discontinuation of Treatment with Lexapro: A gradual reduction in dose rather than abrupt cessation is recommended whenever possible.
- Seizures: Prescribe with care in patients with a history of seizure.
- Activation of Mania/Hypomania: Screen patients for bipolar disorder.
- Hyponatremia: Can occur in association with SIADH
- Abnormal Bleeding: Use caution in concomitant use with NSAIDs, aspirin, warfarin or other drugs that affect coagulation.
- Interference with Cognitive and Motor Performance: Use caution when operating machinery.
- Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants
- Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.
- Sexual Dysfunction: Lexapro may cause symptoms of sexual dysfunction
The following adverse reactions have been identified during post-approval use of Lexapro. 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.
Monoamine Oxidase Inhibitors (MAOIs) and Serotonergic Drugs
The concomitant use of Lexapro with MAOIs intended to treat psychiatric disorders is contraindicated. Lexapro 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 Lexapro. Lexapro should be discontinued before initiating treatment with the MAOI.
If concomitant use of Lexapro with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamine 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 Lexapro and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Lexapro 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 Lexapro 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 Lexapro 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 Lexapro 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 Lexapro and lithium are coadministered.
Pimozide and Celexa: 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 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 Lexapro 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 Lexapro and metoprolol had no clinically significant effects on blood pressure or heart rate.
Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and escitalopram.
USE IN SPECIFIC POPULATIONS
Pregnancy: 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 adaptationwith exposure to selective serotonin reuptake inhibitors (SSRIs), including LEXAPRO, during pregnancy. There are risks associated with untreated depression in pregnancy.
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 SSRIs or SNRIs, including Lexapro, late in 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, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
Lactation: 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 LEXAPRO and any potential adverse effects on the breastfed child from LEXAPRO or from the underlying maternal condition.
Pediatric Use: The safety and effectiveness of Lexapro 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.
The following have been reported with Lexapro 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 Lexapro overdosage ingestions due to the arrhythmia risk.
Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a Lexapro overdose.
Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for overdosage management recommendations.