Black Box Warnings Incite Red Flags

Jeffrey A. Kyle, PharmD, and Jennifer Cortes, PharmD Candidate
Published Online: Thursday, May 1, 2008

Dr. Kyle is an assistant professor of pharmacy practice at the Gregory School of Pharmacy at Palm Beach Atlantic University,West Palm Beach, Florida. Ms. Cortes is a 2009 PharmD candidate at the Gregory School of Pharmacy at Palm Beach Atlantic University,West Palm Beach, Florida.


What is a black box warning? A black box warning, commonly referred to as a boxed warning, is a notification to practitioners from the FDA that 1 of 3 situations has occurred: (1) "There is an adverse reaction so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using a drug"; (2) "There is a serious adverse event reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug"; or (3) "FDA approved the drug with restrictions to assure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted."1

Does this mean that a drug with a black box warning should not be used? No, it does not. The FDA requires the warning to be placed in the package insert so that practitioners can heed the warnings. Medications with a black box warning have either shown or are expected to have a serious adverse event or death. Therefore, patients who are on these medications should be carefully monitored on a regular basis.

Based on a number of both published and unpublished trials, the FDA voted 18 to 5 on September 14, 2004, to issue a black box warning for all selective serotonin reuptake inhibitors (SSRIs) stating: "Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in childrenand adolescents with manic depressive disorder (MDD) and other psychiatric disorders."2 Additionally, it was observed that the increased risk of suicide was higher during the first few months of treatment with an SSRI.3 The initial concern over the increased risk of suicide in children stemmed from reports of suicidal behavior occurring in some paroxetine (Paxil) trials, as well as recommendations from the United Kingdom Medicines and Healthcare Products Regulatory Agency urging that paroxetine not be used in individuals younger than 18 years old.4

The FDA then began an investigation reviewing some 23 trials funded by industry, as well as the Treatment for Adolescents with Depression Study (TADS). The analysis from these 24 trials, which included approximately 4000 patients, overall found that suicidal behavior occurred in 109 patients; in addition, 47 patients were hospitalized and 66 committed harm to themselves, but an actual incidence of suicide was never reported.5

Some of the data collected by the FDA from the 23 unpublished industry-funded trials included the following medications: fluoxetine (Prozac), sertraline (Zoloft), paroxetine, citalopram (Celexa), and venlafaxine (Effexor). Fluoxetine did not show a "suicide/self-harm risk" in 2 trials that were analyzed.5 Another with sertraline had a 4.1% "possibly suicide-related" risk versus 0% in placebo.5 A paroxetine trial revealed a "possibly suicide-related" risk of 6.5% versus 1.1% in placebo; in addition, the trial found 5.4% suicide attempts versus 0% in placebo.5 One citalopram study showed a 13% "possibly suicide-related" risk and suicide attempts versus 8% in placebo.5 Venlafaxine is not considered an SSRI, but it also revealed an increase in "possibly suicide-related" risk and suicide attempts, when compared with placebo.5

Although FDA officials knew of these findings, they contracted experts from Columbia University to review the narratives of adverse events reports and to report the incidence of suicidality from the industry-funded unpublished trials.6 The FDA researchers then compiled all the information into a meta-analysis, and the results revealed that suicide behavior in children was 2 times greater than with placebo.6

The TADS study was a 12-week randomized, placebo-controlled trial that included 439 patients aged 12 to 17 years old with an MDD diagnosis.7 The participants were randomized to one of 4 treatment arms: cognitive-behavioral therapy (CBT) alone, fluoxetine alone (FLX), combination of fluoxetine with CBT, or placebo.7 The study authors concluded that the combination therapy (fluoxetine with CBT) had greater effectiveness in reducing the symptoms of depression.7 In the December 2006 TADS study, safety results were published, and the authors compared the "rates of physical, psychiatric, and suicide-related events in adolescents with MDD treated with [FLX], CBT, combination treatment, or placebo."8 Although the article reported 24 suicide-related events, only 23 cases were documented: 5 in the CBT arm, 10 in the fluoxetine arm, 5 in the combination arm, and 3 with placebo.8

The authors revealed that only 5 actual suicide attempts occurred: 1 in the CBT arm, 2 in the fluoxetine arm, 2 in the combination arm, and 0 in the placebo arm.8 The study concluded that a combination of fluoxetine and CBT is safer than using a medication alone, because, although suicidal ideation improved in all treatment arms, the greatest improvement was seen in the combination treatment arm.8

In trying to assess the risk of suicidal thoughts and behavior in adults, the FDA collected data from 295 trials that included approximately 77,000 patients with MDD and other psychiatric disorders. 9 Then in December 2006, after the information was compiled and interpreted, the FDA?s Psychopharmacologic Drugs Advisory Committee agreed that labeling changes should be made in order to increase awareness of the risk of suicide in young adults.9 The committee also stated that practitioners should be reminded that the use of antidepressants is beneficial in older adults and that underlying psychiatric disorders also can cause an increase in suicidality.

On May 2, 2007, the FDA proposed that all manufacturers update and add a statement of an increased risk of suicidal behavior for individuals aged 18 through 24 years to the black box warning on all antidepressant medications? labeling.9 In addition to the inclusion of a black box warning to the labeling, the FDA recommended that clinicians assess the risk of suicide prior to prescribing an antidepressant in children and adolescents.

At the time an antidepressant is dispensed, the FDA requires that a medication guide be given to each patient. The medication guide includes symptoms that the patient?s family/caregiver should watch for, major counseling points concerning antidepressant medications, and the most important information regarding antidepressants and suicidal behavior. During this time, pharmacists should take the opportunity to review the medication guide with the patient and/or caregiver. Pharmacists also should encourage families to be very observant of their children?s behavior or any unusual change in behavior that may lend itself to suicide, especially during the initial few months of a course of drug therapy, or at times of dose changes. Symptoms such as anxiety, agitation, panic attacks, irritability, hostility, impulsivity, and mania may represent warning signs of suicidal ideation. Patients should be aware of alternative forms of treatment such as CBT. CBT is a "relatively short-term focused psychotherapy for a wide range of psychological problems."10 In children and adolescents, CBT often is used to treat depression, anxiety, obsessive?compulsive disorder, and attention-deficit/hyperactivity disorder, with the ultimate goal of improving one?s quality of life.11

Currently, the only FDA-approved SSRIs for use in pediatrics include fluoxetine for MDD and sertraline, fluoxetine, paroxetine, and fluvoxamine (Luvox) for obsessive?compulsive disorder.12-15 Despite the fact that SSRIs have a black box warning of suicidality for use in children and adolescents, these medications have been proven safe and effective and are still frequently prescribed. Patients with a prior history of suicidal ideation or behavior, however, should have consideration of other options such as CBT before an SSRI is initiated.

References

  1. FDA/CBER resources page. Food and Drug Administration Web site. Available at: www.fda.gov/cber/gdlns/boxwarlb.htm. Accessed January 23, 2008.
  2. Black Box Warnings from Drug Facts & Comparisons page. Facts & Comparisons Web site. Available at: online.factsandcomparisons.com. Accessed January 23, 2008.
  3. Revisions to Product Labeling. FDA Web site. Available at: www.fda.gov/cder/drug/antidepressants/antidepressants_label_change_2007.pdf. Accessed January 23, 2008.
  4. Leslie LK, Newman TB, Chesney PM, Perrin JM. The Food and Drug Administration's deliberation on antidepressant use in pediatric patients. Pediatrics. 2005;116:195-204.
  5. FDA Antidepressant Suicide Warning. McMan's Depression and Bipolar Web site. Available at: www.mcmanweb.com/FDA_suicide.htm. Accessed January 29, 2008.
  6. Newman TB. A black box warning for antidepressants in children? N Engl J Med. 2004;351:1595-8.
  7. March J, Silva S, Petrycki S, et al. Fluoxetine, a cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with depression study (TADS) randomized controlled trial. JAMA. 2004;292:807-20.
  8. Emslie G, Kratochvil C, Vitiello B, et al. Treatment for Adolescents with Depression Study (TADS): safety results. J Am Acad Child Adolesc Psychiatry. 2006;45:1440-55.
  9. FDA News page. Food and Drug Administration Web site. Available at: www.fda.gov/bbs/topics/news/2007/new01624.html. Accessed February 24, 2008.
  10. What is cognitive therapy?. The American Institute for Cognitive Therapy Web site. Available at: www.cognitivetherapynyc.com/default.asp?sid=768. Accessed February 9, 2008.
  11. Child and Adolescent Treatment page. The American Institute for Cognitive Therapy Web site. Available at: www.cognitivetherapynyc.com/child.asp. Accessed February 9, 2008.
  12. Prozac [package insert]. Indianapolis, IN: Eli Lilly and Co; 2008.
  13. Zoloft [package insert]. New York, NY: Roerig, a division of Pfizer, Inc., 2008.
  14. Paxil [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2008.
  15. Luvox [package insert]. Marietta, GA: Solvay Pharmaceuticals, Inc. 2000.


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