FDA is expanding its concerns about the suicide potential of antidepressants in pediatric patients beyond GlaxoSmithKline's Paxil .

The agency issued a ¹ public health advisory Oct. 27 alerting health care professionals "to reports of the occurrence of suicidality (both suicidal ideation and suicide attempts) in clinical trials for various antidepressant drugs in pediatric patients with major depressive disorder."

"FDA has completed a preliminary review of such reports for 8 antidepressant drugs (citalopram [Forest's Celexa ], fluoxetine [Lilly's Prozac ], fluvoxamine [Solvay's Luvox ], mirtazapine [Organon's Remeron ], nefazodone [Bristol-Myers Squibb's Serzone ], paroxetine [Paxil], sertraline [Pfizer's Zoloft ], and venlafaxine [Wyeth's Effexor ]) studied under the pediatric exclusivity provision, and has determined that additional data and analysis, and also a public discussion of available data, are needed."

The advisory was sent through FDA's Medwatch partners to doctors and medical organizations.

"In the 20 placebo-controlled trials being considered for these 8 drugs, involving over 4,100 pediatric patients, there have been no reports of completed suicides," FDA said.

"However, FDA has not at this point been able to rule out an increased risk of suicidality for any of these drugs," the agency added.

Antidepressant labeling carries a class warning noting that "the possibility of a suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy."

FDA emphasized that only Prozac has been shown to be effective in major depressive disorder for pediatric patients.

"For the seven drugs evaluated in pediatric major depressive disorder (MDD), data FDA reviewed were adequate to establish effectiveness in MDD only for Prozac." The agency added, however, that "failure to show effectiveness in any particular study in pediatric MDD, however, is not definitive evidence that the drug is not effective because trials may fail for many reasons."

FDA issued a "Talk Paper" on June 19 cautioning against the off-label use of GSK's Paxil to treat major depressive disorder in pediatric patients due to the possibility of increased risk of suicide thinking and attempts (² Also see "GSK Paxil Pediatric Safety Concerns Have No Effect On Adult Use, FDA Says" - Pink Sheet, 23 June, 2003., p. 6).

GSK conducted a pediatric study comparing Paxil to placebo in 1,600 patients with major depressive disorder, obsessive compulsive disorder and social anxiety disorder. The overall rate of suicidal thinking or suicide attempts in the study was 3.4% for the Paxil group and 1.2% for the placebo group.

The publicity surrounding the suicidality warnings for Paxil contributed to GSK's decision to increase its legal reserves by £150 mil. ($254 mil.) during the quarter.

GSK Chief Financial Officer John Coombe explained during an Oct. 22 conference call that "we provide for all claims notified to us...the amounts we think we will end up settling for....We don't stick our finger in the air and try to guess how many claims might be notified at the end of five years, but we work on the facts that we've been given. We look at it every quarter."

"It's a fact of life in this industry these days that companies like us are going to have regular amounts provided to cover legal exposures. This year...just to give you one example, you've seen a lot of stuff in the press about Paxil," Coombe said.

CEO J.P. Garnier added, "just to be clear though, since we talked last quarter, this does not reflect on any significant new case. It's a lot of the same cost of doing business, so to speak."

A ³ study of Zoloft in 376 pediatric patients with major depressive disorder, published in the Aug. 27 Journal of the American Medical Association, found no statistical difference between placebo and treatment groups in suicide attempts or ideation. Two patients on Zoloft and in the placebo group attempted suicide while three patients on Zoloft experienced suicidal ideation versus none on placebo. Patients who had previously attempted suicide were excluded from the trial.

At the Oct. 29 meeting of its Pediatric Advisory Subcommittee of the Anti-Infective Drugs Advisory Committee, FDA postponed any discussions on suicidality associated with antidepressants during an update on adverse event reports in pediatric patients.

"We know to date, that the data do not clearly establish an association between the use of these drugs and increased suicidal thoughts or actions by pediatric patients. Nevertheless, it is not possible at this point to rule out an increased risk of these adverse events for any of these drugs....Because of this issue, we are deferring review of any of the products in this class until February," FDA Office of Counterterrorism and Pediatric Drug Development Director Dianne Murphy, MD, said.

Antidepressant suicidality in pediatric patients will be the topic of a Feb. 2, 2004 meeting of FDA's Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee [To ⁴ watch a webcast or video of this meeting, go to FDAAdvisoryCommittee.com].

Adverse event reports other than suicidality were discussed for Serzone at the Oct. 29 meeting. From June 27, 2002 to July 27, 2003, there were three "unduplicated" serious pediatric adverse event reports for Serzone and no deaths. The events included congenital hand malformation in an infant, potential arrhythmia and agitation after accidental ingestion, and Crohn's disease and sclerosing cholangitis (infection of the biliary tree) in a 14-year old girl.

FDA noted that both pediatric and adult prescriptions for Serzone declined from 1999 to 2003, with pediatric use declining more than 50% in children since pediatric exclusivity was granted.

Public Citizen's Health Research Group has been pushing for Serzone removal from the market because of deaths and severe injuries from liver failure.

On Oct. 29, the group filed a ⁵ supplement to its March petition, which called for a ban on the product due to severe side effects and because the drug offers no unique therapeutic benefit (⁶ Also see "Public Citizen Wants Serzone Pulled; No “Unique” Benefit To Offset Risk" - Pink Sheet, 10 March, 2003., p. 17). The supplement notes that Canada decided to remove Serzone from the market on Oct. 2, 2003 after receiving 51 reports of hepatotoxicity through December 2002.

HRG said that a search of FDA's Adverse Event Reports database found 41 cases of liver injury and 9 deaths related to Serzone from April 2002 to May 2003. "We found almost as many deaths from liver failure reported in the last 14 months we examined as in the 7 previous years (9 vs. 11)," HRG said.

FDA Expands Pediatric Suicidality Caution To Antidepressants Beyond Paxil

More from Archive

More from Pink Sheet