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:

(sye TAL oh pram)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

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. Use caution in patients 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.

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. Citalopram is not FDA approved for use in children.

Use with caution in patients with hepatic or renal dysfunction, in elderly patients, concomitant CNS depressants, and pregnancy (high doses of citalopram have 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. May cause hyponatremia/SIADH. May cause or exacerbate sexual dysfunction. Upon discontinuation of citalopram 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: Somnolence, insomnia

Gastrointestinal: Nausea, xerostomia

Miscellaneous: Diaphoresis

<10%:

Central nervous system: Anxiety, anorexia, agitation, yawning

Dermatologic: Rash, pruritus

Endocrine & metabolic: Sexual dysfunction

Gastrointestinal: Diarrhea, dyspepsia, vomiting, abdominal pain, weight gain

Neuromuscular & skeletal: Tremor, arthralgia, myalgia

Respiratory: Cough, rhinitis, sinusitis

<1%, postmarketing, and/or case reports: Acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, grand mal seizure, hemolytic anemia, hepatic necrosis, myoclonus, neuroleptic malignant syndrome, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, serotonin syndrome, SIADH, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, withdrawal syndrome

Overdosage/Toxicology:

Drug Interactions:

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

Beta-blockers: Citalopram may increase levels of some beta-blockers (see Carvedilol and Metoprolol); monitor carefully

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

Carbamazepine: May enhance the metabolism of citalopram

Carvedilol: Serum concentrations may be increased; monitor carefully for increased carvedilol effect (hypotension and bradycardia)

Cimetidine: May inhibit the metabolism of citalopram

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

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

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

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

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

Ritonavir: Combined use of citalopram with ritonavir may cause serotonin syndrome in HIV-positive patients; 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

Serotonin reuptake inhibitors: 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

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:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Distribution: Vd: 12 L/kg

Protein binding, plasma: ~80%

Metabolism: Extensively hepatic, including CYP, to N-demethylated, N-oxide, and deaminated metabolites

Bioavailability: 80%

Half-life elimination: 24-48 hours; average 35 hours (doubled with hepatic impairment)

Time to peak, serum: 1-6 hours, average within 4 hours

Excretion: Urine (10% as unchanged drug)

Note: Clearance was decreased, while AUC and half-life were significantly increased in elderly patients and in patients with hepatic impairment. Mild to moderate renal impairment may reduce clearance (17%) and prolong half-life of citalopram. No pharmacokinetic information is available concerning patients with severe renal impairment.

Dosage:

Children and Adolescents: OCD (unlabeled use): 10-40 mg/day

Adults: Depression: Initial: 20 mg/day, generally with an increase to 40 mg/day; doses of more than 40 mg are not usually necessary. Should a dose increase be necessary, it should occur in 20 mg increments at intervals of no less than 1 week. Maximum dose: 60 mg/day; reduce dosage in elderly or those with hepatic impairment.

Monitoring Parameters:

Dietary Considerations:

Patient Education:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Dental Comment:

Mental Health: Child/Adolescent Considerations:

Thomsen PH, "Child and Adolescent Obsessive-Compulsive Disorder Treated With Citalopram: Findings From an Open Trial of 23 Cases,"J Child Adolesc Psychopharmacol, 1997, 7(3):157-66.

Dosage Forms:

Solution, oral: 10 mg/5 mL (240 mL) [alcohol free, sugar free; peppermint flavor]

Tablet: 10 mg, 20 mg, 40 mg

International Brand Names: