FDA Safety Labeling Changes: Strattera, Antidepressants

Yael Waknine

May 11, 2005

May 11, 2005 — The U.S. Food and Drug Administration (FDA) approved in February revisions to safety labeling to advise that use of atomoxetine HCl may be linked rarely to severe liver injury, and that use of drugs approved to treat major depressive disorder is associated with an increased risk of suicidality in children and adolescents.

Atomoxetine HCl (Strattera) Linked Rarely to Severe Liver Injury

On Feb. 14, the FDA approved revisions to the safety labeling for atomoxetine HCl capsules (Strattera, made by Eli Lilly and Co.) to warn of the risk of severe liver injury associated with its use.

The FDA has received two reports of severe liver injury and jaundice in the absence of other explanatory factors in patients receiving atomoxetine. In one patient, elevated levels of hepatic enzymes (up to 40 times the upper limit of normal [ULN]) and bilirubin (up to 12 times the ULN) recurred upon rechallenge. Both patients recovered upon discontinuation of therapy without requiring liver transplantation.

The FDA notes that such reactions may occur several months after therapy initiation, and laboratory abnormalities may continue to worsen for several weeks after discontinuation. Due to probable underreporting, the true incidence of these adverse events remains unknown.

In a small percentage of patients, the FDA warns, severe drug-related liver injury may progress to acute liver failure resulting in death or the need for liver transplantation.

Liver enzyme levels should be immediately evaluated in patients receiving atomoxetine who present with signs or symptoms of liver dysfunction such as pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms. Therapy should be discontinued permanently in patients with jaundice or laboratory evidence of liver injury.

Atomoxetine HCl is indicated for the treatment of attention deficit/hyperactivity disorder.

Antidepressant Use in Children, Adolescents Linked to Increased Risk of Suicidality

On Feb. 18, the FDA approved revisions to the safety labeling for drugs approved to treat major depressive disorder (MDD), warning of the increased risk of suicidal thinking and behavior (suicidality) associated with their use in children and adolescents.

Pediatric patients with MDD may experience worsening of their depression and/or emergence of suicidal ideation and behavior or unusual changes in behavior until significant remission occurs — regardless of whether antidepressants are being taken.

The warning was based on a pooled analysis of data from 24 short-term (up to four months), placebo-controlled trials of nine antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) in more than 4,400 children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders.

The analysis revealed that treatment with antidepressants significantly increased the mean risk of adverse events representing suicidality in this population compared with placebo (4% vs 2%), and that this risk was greater during the first few months of treatment. No suicides occurred in any of the trials.

It is unknown whether the suicidality risk in pediatric patients extends to longer-term use (beyond several months) or to adults.

The FDA advises use of antidepressants in children and adolescents only when the potential benefit outweighs the increased risk of suicidality. Pediatric patients receiving antidepressant therapy should be monitored closely for clinical worsening, suicidality, and unusual changes in behavior — particularly during the initial few months of therapy and when dose changes.

Monitoring should include weekly face-to-face contact with patients or their family members/caregivers during the first month of treatment, thencontact every other week for the next month, once at three months, and thereafter as clinically indicated.

Similar monitoring is recommended for adults with MDD or comorbid depression in the setting of another psychiatric illness being treated with antidepressants. The FDA notes that consideration should be given to changing or discontinuing the therapeutic regimen in patients with persistently worsening depression or suicidality that is newly emergent, severe, or abrupt in onset.

The warning applies to safety labeling for citalopram HBr tablets and oral solution (Celexa, made by Forest Laboratories, Inc.); duloxetine HCl delayed-release capsules (Cymbalta, made by Eli Lilly and Co.); venlafaxine HCl tablets and extended-release tablets (Effexor and Effexor XR, made by Wyeth Pharmaceuticals, Inc.); and escitalopram tablets and oral solution (Lexapro, made by Forest Laboratories, Inc.).

The warning also applies to safety labeling for phenelzine sulfate tablets (Nardil, made by Pfizer Pharmaceuticals); fluoxetine HCl tablets, capsules, and oral solution (Prozac, made by Eli Lilly and Co.); fluoxetine HCl capsules (Sarafem, made by Eli Lilly and Co.); doxepin HCl capsules and oral concentrate (Sinequan, made by Pfizer Pharmaceuticals); olanzapine plus fluoxetine HCl capsules (Symbyax, made by Eli Lilly and Co.); and sertraline HCl tablets and oral concentrate (Zoloft, made by Pfizer Pharmaceuticals).

The FDA notes that only fluoxetine is approved for use in treating MDD in pediatric patients. Drugs approved for treating pediatric OCD include fluoxetine, sertraline, fluvoxamine maleate (Luvox, made by Solvay Pharmaceuticals), and clomipramine HCl (Anafranil, made by Mallinckrodt, Inc.). None of the drugs are approved for other pediatric psychiatric indications.

Reviewed by Gary D. Vogin, MD

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