FDA Issues Public Health Advisory for Antidepressant Use in Children and Adolescents

Yael Waknine

October 15, 2004

Oct. 15, 2004 — The U.S. Food and Drug Administration (FDA) today issued a public health advisory to warn of the increased risk of suicidality associated with use of antidepressants in children and adolescents. The advisory lists several strategies to alert the public and healthcare professionals of this warning, including labeling changes, the dispensing of a patient medication guide (MedGuide) with each prescription filled, and implementation of "unit of use" packaging. These actions are consistent with recommendations made to the FDA at a joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Drugs Advisory Committee on Sept. 13-14, 2004.

The FDA has directed manufacturers via letter to revise the safety labeling of all antidepressant drugs to include "black box" and expanded warnings of the increased risk of suicidality and updated results of pediatric studies, according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program.

The FDA has also informed antidepressant manufacturers that a MedGuide is to be dispensed with the medication to advise patients and their parents or caregivers of the risk and precautions that may be taken. The FDA plans to work closely with the manufacturers of all approved antidepressant products to implement "unit of use" packaging to ensure that a MedGuide is included with every prescription or refill.

The advisory was based on an analysis of data from 24 short-term, placebo-controlled trials of nine antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), and involving 4,400 children and adolescents being treated for major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and other psychiatric disorders. Results showed an increased risk of suicidality (suicidal thoughts and/or behavior) in the treatment groups compared with placebo (4% vs 2%).

The FDA advises that the risk of increased suicidality be considered with respect to clinical need before initiating antidepressant therapy in children and adolescents with MDD and other psychiatric disorders, and that prescriptions be written for the lowest possible quantity of tablets to reduce the risk of overdose.

Families and caregivers should closely observe pediatric patients being treated with antidepressants for signs of clinical worsening, suicidality, agitation, irritability, and unusual changes in behavior, especially during the first few months after initiation of therapy and upon dosing changes. Daily monitoring and close contact with the prescribing physician are advised.

The new antidepressant labeling will include a statement regarding its approved pediatric indication(s). Of the antidepressants, only fluoxetine (Prozac) is approved for use in treating MDD in pediatric patients. Fluoxetine, sertraline (Zoloft), fluvoxamine (Luvox), and clomipramene (Anafranil) are approved for OCD in pediatric patients. None of the drugs is approved for other psychiatric indications in children.

The FDA notes that these labeling changes apply to the entire category of antidepressants due to a lack of available data to exclude any given drug from the associated increased risk of suicidality.

Affected products include: clomipramine (Anafranil [Mallinckrodt]), nortriptyline (Aventyl [Eli Lilly], Pamelor [Mallinckrodt]), citalopram (Celexa [Pfizer]), duloxetine (Cymbalta [Eli Lilly]), trazodone (Desyrel), venlafaxine (Effexor [Wyeth]), amitriptyline (Elavil [Merck]), escitalopram (Lexapro [Forest]), chlordiazepoxide/amitriptyline (Limbitrol [Valeant]), maprotiline (Ludiomil), fluvoxamine (Luvox), isocarboxazid (Marplan), phenelzine (Nardil [Pfizer]), desipramine (Norpramin [Aventis]), tranylcypromine (Parnate [GlaxoSmithKline]), paroxetine (Paxil [GlaxoSmithKline], Pexeva [Synthon]), fluoxetine (Prozac [Dista], Sarafem [Eli Lilly]), mirtazapine (Remeron [Organon]), nefazodone (Serzone [Bristol-Myers Squibb]), doxepin (Sinequan [Pfizer]), trimipramine (Surmontil [Odyssey]), olanzapine/fluoxetine (Symbyax [Eli Lilly]), imipramine (Tofranil, Tofranil-PM [Mallinckrodt]), perphenazine/amitriptyline (Triavil [Merck]), protriptyline (Vivactil [Odyssey]), bupropion (Wellbutrin, Zyban [GlaxoSmithKline]), and sertraline (Zoloft [Pfizer]).

More information concerning the antidepressant labeling changes can be obtained on the FDA's Web site at: https://www.fda.gov/cder/drug/antidepressants/default.htm.

Reviewed by Gary D. Vogin, MD


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