The Food and Drug Administration has issued an update to provide health care providers and patients with the most current information on the use of antidepressants in pediatric patients.
FDA has completed a new analysis of pediatric suicidality (suicidal thoughts and actions) data submitted to the agency and will be posting its analysis on its web site. FDA will also be posting on its web site additional summaries of pediatric efficacy studies from drugs that have been studied in depression in pediatric patients. Although specific new labeling language has yet to be developed, FDA will assure that the labels of the antidepressants used in pediatric patients reflect the most recent information obtained from these studies and analyses.
Next month, on September 13 and 14, 2004, FDA officials will be discussing this issue at a public meeting of its Psychopharmacologic Drugs and Pediatric Advisory Committees, at which time the agency will hear from the public and solicit the advice of the committees on these labeling changes and other possible regulatory actions.
FDA has been closely reviewing the results of antidepressant studies in children since June 2003, after an initial report on studies with paroxetine (Paxil) appeared to suggest an increased risk of suicidal thoughts and actions in the children given Paxil, compared to those given placebo. Later reports on studies of other drugs supported the possibility of an increased risk of suicidal thoughts and actions in children taking these drugs. There were no suicides in any of the trials.
FDA has closely examined the studies of the antidepressants because of the potential public health impact of a link between the drugs and suicidality and the importance of these drugs in treating depression and other serious mental health conditions. On close examination of the initial reports of suicidality, it was unclear whether some of the identified suicidal behaviors reported in these studies represented actual suicide attempts or self-injurious behavior that was not suicide-related. FDA therefore arranged with Columbia University suicidality experts to review these reports.
Meanwhile, FDA brought the available information to its Psychopharmacologic Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committees on February 2, 2004. The advisory committee members advised FDA that even before the Columbia analysis was complete, the labeling should draw more attention to the need to monitor patients closely when antidepressant therapy is initiated. Based on this recommendation, FDA asked manufacturers to change the labels of ten drugs to include stronger cautions and warnings about the need to monitor patients for worsening of depression and the emergence of suicidality, whether such worsening represents an adverse effect of the drug or failure of the drug to prevent such worsening. The new warning language has now been added to the labels for seven of these products. Sponsors for the other three drugs have agreed to adopt the language.
Because of concerns about whether the varied events identified by sponsors under the broad category of "possibly suicide-related" could all reasonably be considered to represent suicidality, FDA asked Columbia University to assemble an international panel of pediatric suicidality experts to undertake a blinded review of the reported behaviors using a rigorous classification system. The Columbia group submitted its completed review to FDA last month.
FDA has developed its analysis of the pediatric suicidality data, based on case classifications provided by Columbia University, and will be posting the analysis on its web site. While there are findings among these data suggestive of an increased risk of suicidality for some of these drugs, there remain inconsistencies in the results, both across trials for individual drugs and across drugs. Thus, an overall interpretation of these findings represents a substantial challenge.
FDA's next step, planned for some time, will be to update the Psychopharmacologic Drugs and the Pediatric Advisory Committees about the results of these reviews and to seek assistance from the committees in interpreting the data and in considering what additional regulatory actions may be needed to promote the safe use of these drugs.
Why is FDA recommending that Paxil not be used for the treatment of pediatric major depressive disorder (MDD)?
FDA is currently reviewing reports of an increased risk of suicidal thinking and suicide attempts related to the use of the drug Paxil in children and adolescents under the age of 18 with MDD. Although FDA has not completed this evaluation, we are recommending that Paxil not be used in the treatment of pediatric MDD. There is no evidence that Paxil is effective in children or adolescents with MDD.
Should children using Paxil stop taking it immediately?
It is very important that children and adolescents not stop taking Paxil suddenly, as there is a risk of discontinuation effects. Caretakers of children and adolescents currently taking Paxil should consult their doctor to discuss the best course of action. If they are doing well on Paxil, their doctor may advise that they complete their course of treatment. If their doctor advises that Paxil should be stopped, this should be done gradually to minimize the risk of discontinuation effects. If the dose is not reduced gradually, there is a greater chance of experiencing side effects. If severe unwanted side effects occur, it may be necessary to start taking Paxil again or increase the dose before subsequently decreasing the dose more gradually.
What data is the advice based on?
Three well-controlled clinical trials carried out in children (under 18 years of age) with MDD compared the effect of Paxil and placebo (sugar pills) and found that Paxil did not work any better than placebo in the treatment of MDD.
Based on the results of the new analyses of safety data from pediatric studies, it was found that certain possibly suicide-related behaviors, including suicidal thoughts and attempts, were more common in children receiving Paxil. The risk of these events in the study was about 3 times greater with Paxil compared to placebo. There were no deaths in these trials.
Is Paxil approved for the treatment of children and adolescents?
The FDA has not approved Paxil for the treatment of MDD or any other indication in pediatric patients. However, the FDA does not regulate the practice of medicine and physicians may use a drug in ways other than indicated on the labeling when, in their professional judgment, it is warranted in a particular case.
My child is taking Paxil for a condition other than depression. What should I do?
Paxil has not been approved for use in children under the age of 18 for any indication, but your child may have been prescribed Paxil for an off-label use. As stated above, physicians may use a drug in ways other than indicated on the labeling when, in their professional judgment, it is warranted in a particular case. If your child is taking Paxil, you should consult with your doctor before making any changes. It is very important that Paxil not be stopped abruptly since discontinuation effects may occur.
What does this mean for the use of Paxil in adults?
Paxil is approved for use in adults for the following indications: major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and post-traumatic stress disorder. Extensive analyses of the data from studies of Paxil in adults and from postmarketing adverse event reports have not revealed an increase in the rate of suicidal thoughts or suicide attempts compared to placebo.
What advice can you provide to adults using Paxil?
It is vital that patients are not panicked into stopping their medication suddenly. The advice to adults using Paxil has not changed. Paxil has been demonstrated to be effective in treatment of major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and post-traumatic stress disorder in adults. Anyone taking Paxil who is feeling unwell or is concerned about the treatment should consult his or her doctor.
Why would Paxil cause these reactions in children and not in adults?
Childhood depression is different from adult depression. The reasons are not clear but could relate to the continuing development of the child’s brain. It has been difficult to show effectiveness in children of antidepressants known to work in adults and a number of effective adult antidepressants have not been shown to work in childhood depression Children may also react very differently to some medicines and some side effects over a range of drugs are seen in children that are not seen in adults.
However, the Agency has not yet definitively determined that there is an increased risk of suicidal behavior in pediatric patients with MDD treated with Paxil.
Are there drugs approved for the treatment of depression in children?
Prozac (fluoxetine) is the only drug approved for the treatment of major depressive disorder in children. It is approved in children 8 to 18 years of age.
What is Paxil?
Paxil (paroxetine) is one of a class of medicines called Selective Serotonin Reuptake Inhibitors (SSRIs). These drugs increase the activity of an important brain chemical called serotonin, a chemical know to be deficient in patients with MDD.
How long has Paxil been on the market?
Paxil was first approved in the United States on December 29, 1992, for the treatment of depression.