Special Alerts:

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Pronunciation:
(es sye TAL oh pram)(es sye TAL oh pram)

U.S. Brand Names: Lexapro™

Synonyms: Escitalopram Oxalate; Lu-26-054; S-Citalopram

Generic Available: No

Use: Treatment of major depressive disorder; generalized anxiety disorders (GAD)

Pregnancy Risk Factor: C

Pregnancy Implications: Teratogenic effects have been reported in animal studies. Nonteratogenic effects including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor have been reported in the neonate immediately following delivery after exposure late in the third trimester. Adverse effects may be due to toxic effects of SSRI or drug discontinuation. In some cases, may present clinically as serotonin syndrome. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus. If treatment during pregnancy is required, consider tapering therapy during the third trimester.

Lactation: Enters breast milk/not recommended

Contraindications: Hypersensitivity to escitalopram, citalopram, or any component of the formulation; concomitant use or within 2 weeks of MAO inhibitors

Warnings/Precautions: Potential for severe reaction when used with MAO inhibitors; serotonin syndrome (hyperthermia, muscular rigidity, mental status changes/agitation, autonomic instability) may occur. May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients should be screened for bipolar disorder, since using antidepressants alone may induce manic episodes with this condition. Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Escitalopram is not FDA approved for use in children.

Use caution with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold.

May cause hyponatremia/SIADH. May cause or exacerbate sexual dysfunction. Use caution with renal or liver impairment; concomitant CNS depressants; pregnancy (high doses of citalopram has been associated with teratogenicity in animals). Use caution with concomitant use of NSAIDs, ASA, or other drugs that affect coagulation; the risk of bleeding is potentiated.

Upon discontinuation of escitalopram therapy, gradually taper dose. If intolerable symptoms occur following a decrease in dosage or upon discontinuation of therapy, then resuming the previous dose with a more gradual taper should be considered. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed not to abruptly discontinue this medication, but notify their healthcare provider if any of these symptoms or worsening depression occur.

Adverse Reactions:

>10%:

Central nervous system: Headache (24%), somnolence (6% to 13%), insomnia (9% to 12%)

Gastrointestinal: Nausea (15%)

Genitourinary: Ejaculation disorder (9% to 14%)

1% to 10%:

Cardiovascular: Chest pain, hypertension, palpitation

Central nervous system: Dizziness (5%), fatigue (5% to 8%), dreaming abnormal, concentration impaired, fever, irritability, lethargy, lightheadedness, migraine, vertigo, yawning

Dermatologic: Rash

Endocrine & metabolic: Libido decreased (3% to 7%), anorgasmia (2% to 6%), hot flashes, menstrual cramps, menstrual disorder

Gastrointestinal: Diarrhea (8%), xerostomia (6% to 9%), appetite decreased (3%), constipation (3% to 5%), indigestion (3%), abdominal pain (2%), abdominal cramps, appetite increased, flatulence, gastroenteritis, gastroesophageal reflux, heartburn, toothache, vomiting, weight gain/loss

Genitourinary: Impotence (3%), urinary tract infection, urinary frequency

Neuromuscular & skeletal: Arthralgia, limb pain, muscle cramp, myalgia, neck/shoulder pain, paresthesia, tremor

Ocular: Blurred vision

Otic: Earache, tinnitus

Respiratory: Rhinitis (5%), sinusitis (3%), bronchitis, cough, nasal or sinus congestion, sinus headache

Miscellaneous: Diaphoresis (4% to 5%), flu-like syndrome (5%), allergy

<1%: Abdominal discomfort, acne, agitation, alopecia, amnesia, anaphylaxis, anemia, anxiety attack, apathy, arthritis, arthropathy, asthma, auditory hallucination, back discomfort, belching, bilirubin increased, bloating, bradycardia, bruise, bruxism, carbohydrate craving, carpal tunnel syndrome, chest tightness, chills, confusion, conjunctivitis, crying abnormal, depersonalization, depression aggravated, depression, dermatitis, dry eyes, dry skin, dysequilibrium, dyspepsia, dysuria, ECG abnormal, eczema, edema, emotional lability, excitability, eye infection, eye irritation, faintness, feeling unreal, flushing, folliculitis, forgetfulness, furunculosis, gagging, gastritis, gout, hematoma, hemorrhoids, hypercholesterolemia, hyperglycemia, hyper-reflexia, jaw pain, jaw stiffness, jitteriness, joint stiffness, kidney stone, laryngitis, leg pain, lipoma, malaise, menorrhagia, muscle contractions (involuntary), muscle stiffness, muscle weakness, muscular tone increased, nervousness, nosebleed, panic reaction, pelvic inflammation, pneumonia, pruritus, pupils dilated, restless legs, restlessness aggravated, shaking, shortness of breath, spotting between menses, stool frequency increased, suicidal tendency, suicide attempt, syncope, tachycardia, taste alteration, tics, tracheitis, tremulousness nervous, twitching, urinary frequency, varicose vein, vision abnormal, visual disturbance, weakness

Postmarketing and/or case reports: Acute renal failure, akathisia, angioedema, choreoathetosis, delirium, dyskinesia, epidermal necrolysis, erythema multiforme, grand mal seizure, hemolytic anemia, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, serotonin syndrome, thrombocytopenia, thrombosis, torsade de pointes, ventricular arrhythmia, withdrawal syndrome

Overdosage/Toxicology: Treatment should be symptom-directed and supportive.

Drug Interactions: Substrate (major) of CYP2C19, 3A4; Inhibits CYP2D6 (weak)

Aspirin: Concomitant use of escitalopram and NSAIDs, aspirin, or other drugs affecting coagulation has been associated with an increased risk of bleeding; monitor.

Buspirone: Concurrent use of citalopram with buspirone may cause serotonin syndrome; avoid concurrent use.

Cimetidine: May inhibit the metabolism of citalopram.

CYP2C19 inducers: May decrease the levels/effects of escitalopram. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

CYP2C19 inhibitors: May increase the levels/effects of escitalopram. Example inhibitors include delavirdine, fluconazole, fluvoxamine, gemfibrozil, isoniazid, omeprazole, and ticlopidine.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of escitalopram. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of escitalopram. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Desipramine: Escitalopram may increase desipramine levels.

Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided.

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with MAO inhibitors (serotonin syndrome); this combination should be avoided.

Meperidine: Combined use theoretically may increase the risk of serotonin syndrome.

Metoprolol: Escitalopram may increase plasma levels of metoprolol; monitor for increased effect.

Moclobemide: Concurrent use of citalopram with moclobemide may cause serotonin syndrome; avoid concurrent use.

Nefazodone: Concurrent use of citalopram with nefazodone may cause serotonin syndrome.

NSAIDs: Concomitant use of escitalopram and NSAIDs, aspirin, or other drugs affecting coagulation has been associated with an increased risk of bleeding; monitor.

Selegiline: Concurrent use with citalopram has been reported to cause serotonin syndrome; as an MAO type B inhibitor, the risk of serotonin syndrome may be less than with nonselective MAO inhibitors, and reports indicate that this combination has been well tolerated in Parkinson's patients.

SSRIs: Concurrent use with other reuptake inhibitors may increase the risk of serotonin syndrome.

Sibutramine: May increase the risk of serotonin syndrome with SSRIs.

Sumatriptan (and other serotonin agonists): Concurrent use may result in toxicity; weakness, hyper-reflexia, and incoordination have been observed with sumatriptan and SSRIs. In addition, concurrent use may theoretically increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan.

Tramadol: Concurrent use of citalopram with tramadol may cause serotonin syndrome; avoid concurrent use.

Trazodone: Concurrent use of citalopram with trazodone may cause serotonin syndrome.

Venlafaxine: Combined use with citalopram may increase the risk of serotonin syndrome.

Warfarin: Use with caution; may increase risk of bleeding.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava, and gotu kola (may increase CNS depression).

Stability: Store at 25°C (77°F).

Mechanism of Action: Escitalopram is the S-enantiomer of the racemic derivative citalopram, which selectively inhibits the reuptake of serotonin with little to no effect on norepinephrine or dopamine reuptake. It has no or very low affinity for 5-HT1-7, alpha- and beta-adrenergic, D1-5, H1-3, M1-5, and benzodiazepine receptors. Escitalopram does not bind or has low affinity for Na⁺, K⁺, Cl^-, and Ca⁺⁺ ion channels.

Pharmacodynamics/Kinetics:

Protein binding: 56% to plasma proteins

Metabolism: Hepatic via CYP2C19 and 3A4 to an active metabolite, S-desmethylcitalopram (S-DCT; 1/7 the activity); S-DCT is metabolized to S-didesmethylcitalopram (S-DDCT; active; 1/27 the activity) via CYP2D6

Half-life elimination: Escitalopram: 27-32 hours; S-desmethylcitalopram: 59 hours

Time to peak: Escitalopram: 5 ± 1.5 hours; S-desmethylcitalopram: 14 hours

Excretion: Urine (Escitalopram: 8%; S-DCT: 10%)

Clearance: Total body: 37-40 L/hour; Renal: Escitalopram: 2.7 L/hour; S-desmethylcitalopram: 6.9 L/hour

Dosage: Oral:

Adults: Depression, GAD: Initial: 10 mg/day; dose may be increased to 20 mg/day after at least 1 week

Elderly: 10 mg/day; bioavailability and half-life are increased by 50% in the elderly

Dosage adjustment in renal impairment:

Mild to moderate impairment: No dosage adjustment needed

Severe impairment: Clcr<20 mL/minute: Use caution

Dosage adjustment in hepatic impairment: 10 mg/day

Administration: Administer once daily (morning or evening), with or without food.

Monitoring Parameters: Mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; akathisia

Dietary Considerations: May be taken with or without food.

Patient Education: Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Take exactly as directed; do not alter dose or discontinue without consulting prescriber (effects of medication may take up to 3 weeks to occur). Avoid other stimulants: caffeine or alcohol. May cause dizziness, lightheadedness, insomnia, impaired concentration, headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, loss or increase of appetite, indigestion, or heartburn (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); constipation (increased dietary fluid, fruit, fiber, and increased exercise may help); sexual dysfunction (reversible when drug is discontinued); hot flashes or menstrual cramps; or muscle pain, cramps, or tremor (consult prescriber for approved analgesia). Report immediately any CNS changes such as increased depression, confusion, impaired concentration, severe headache, insomnia, nightmares, irritability, acute anxiety, panic attacks, or thoughts of suicide; persistent GI changes; chest pain or palpitations; blurred vision or vision changes; ringing in ears; unusual cough; or other persistent adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Additional Information: The tablet and oral solution dosage forms are bioequivalent. Clinically, escitalopram 20 mg is equipotent to citalopram 40 mg. Do not coadminister with citalopram.

Dental Health: Effects on Dental Treatment: Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and toothache.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions: Although caution should be used in patients taking tricyclic antidepressants, no interactions have been reported with vasoconstrictors and escitalopram, a nontricyclic antidepressant which acts to increase serotonin.

Dosage Forms:

Solution, oral: 1 mg/mL (240 mL) [peppermint flavor]

Tablet: 5 mg, 10 mg, 20 mg

References:

Bernard L, Stern R, Lew D, et al, "Serotonin Syndrome After Concomitant Treatment With Linezolid and Citalopram,"Clin Infect Dis, 2003, 36(9):1197.

Mahlberg R, Kunz D, Sasse J, et al, "Serotonin Syndrome With Tramadol and Citalopram,"Am J Psychiatry, 2004, 161(6):1129.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings,"Chest, 2003, 123(3):897-922.

Montgomery SA, Loft H, Sanchez C, et al, "Escitalopram (S-Enantiomer of Citalopram): Clinical Efficacy and Onset of Action Predicted From a Rat Model,"Pharmacol Toxicol, 2001, 88(5):282-6.

Tahir N, "Serotonin Syndrome as a Consequence of Drug-Resistant Infections: An Interaction Between Linezolid and Citalopram, J Am Med Dir Assoc, 2004, 5(2):111-3.

von Moltke LL, Greenblatt DJ, Giancarlo GM, et al, "Escitalopram (S-Citalopram) and its Metabolites in vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram,"Drug Metab Dispos, 2001, 29(8):1102-9.

International Brand Names: Cipralex�(r) (AT, CH, DE, DK, FI, GB, HR, IL, IT, NO, SE, SI); Entact�(r) (IT); Lexapro�(r) (IE, NZ); Seroplex�(r) (FR); Sipralexa�(r) (BE)