What is the "Black Box Warning" for Antidepressants?

Question: What is the "Black Box Warning" for Antidepressants?

Answer: On October 15, 2004, after analyzing data from short-term clinical trials on the connection between the use of antidepressants in children and an increased risk of suicide and suicidal thinking, the US Food and Drug Administration (FDA) sent a letter to drug manufacturers ordering them to add a "black box" warning to prescribing information for antidepressants. The warning must read as follows:

Suicidality in Children and Adolescents

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Drug Name] or any other antidepressant in a child or adolescent must balance this risk 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 of the need for close observation and communication with the prescriber. [Drug Name] is not approved for use in pediatric patients except for patients with [Any approved pediatric claims here]. (See Warnings and Precautions: Pediatric Use)

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

The drugs which must carry this warning include:

• Anafranil (clomipramine HCl)
• Aventyl (nortriptyline HCl)
• Celexa (citalopram HBr)
• Cymbalta (duloxetine HCl)
• Desyrel (trazodone HCl)
• Effexor (venlafaxine HCl)
• Elavil (amitriptyline HCl)
• Lexapro (escitalopram oxalate)
• Limbitrol (chlordiazepoxide/amitriptyline)
• Ludiomil (Maprotiline HCl)
• Luvox (fluvoxamine maleate)
• Marplan (isocarboxazid)
• Nardil (phenelzine sulfate)
• Norpramin (desipramine HCl)
• Pamelor (nortriptyline HCl)
• Parnate (tranylcypromine sulfate)
• Paxil (paroxetine HCl)
• Pexeva (paroxetine mesylate)
• Prozac (fluoxetine HCl)
• Remeron (mirtazapine)
• Sarafem (fluoxetine HCl)
• Serzone (nefazodone HCl) (since withdrawn from US market)
• Sinequan (doxepin HCl)
• Surmontil (trimipramine)
• Symbyax (olanzapine/fluoxetine)
• Tofranil (imipramine HCl)
• Tofranil-PM (impiramine pamoate)
• Triavil (Perphenaine/Amitriptyline)
• Vivactil (protriptyline HCl)
• Wellbutrin (bupropion HCl)
• Zoloft (sertraline HCl)
• Zyban (bupropion HCl)

In addition, the FDA mandated new language for the WARNINGS-Clinical Worsening and Suicide Risk section of product information. This language includes:

• a statement that a cause-and-effect relationship has been established between pediatric use and an increased risk of suicide
• statements that both pediatric and adult patients using any of these drugs should be closely monitored
• a list of symptoms that may precede emerging suicidality
• a reminder that bipolar disorder may initially present as depression

and several other related warnings.

References and Additional Information:

Food and Drug Administration. (2004). Labeling Change Request Letter for Antidepressant Medications. Retrieved 8/31/06 from http://www.fda.gov/cder/drug/antidepressants/SSRIlabelChange.htm
Food and Drug Administration. (2004). FDA Public Health Advisory: Suicidality in Children and Adolescents Being Treated With Antidepressant Medications. Retrieved 8/31/06 from http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm