Please refer to your new drug applications submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for [Drug Name].
We additionally refer to the September 13, and 14, 2004 meeting of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee to discuss reports of the occurrence of suicidality in clinical trials for various antidepressant drugs in pediatric patients with major depressive disorder and other psychiatric disorders.
Based upon the recommendations made by the committee members, we believe that additional labeling changes are warranted in order to caution practitioners, patients, family members or caregivers about an increased risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders who are taking antidepressant medications.
Therefore, we are requesting revisions to your labeling in order to incorporate the committee's recommendations. Specifically, we are requesting the following changes to product labeling.
[This new section should be added to the beginning of the package insert with bolded font and enclosed in a black box]
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 following language would replace the current language under the WARNINGS-Clinical Worsening and Suicide Risk section.]
WARNINGS-Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients.
Pooled analyses of short-term placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (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%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied.The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Ideally, such observation would include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then visits every other week for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for [Drug Name] should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.
[This language will be included for those drugs for which tapering is recommended.] If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION -- Discontinuation of Treatment with [Drug Name], for a description of the risks of discontinuation of [Drug Name].
Rule out bipolar disorder to the extent possible: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
[The following language would replace the current language under the PRECAUTIONS- Information for Patients section.]
PRECAUTIONS-Information for Patients
Physicians should inform patients and caregivers about the benefits and risks associated with treatment with [Drug Name] and should counsel them in its appropriate use. A patient Medication Guide is available for [Drug Name] . The prescriber should instruct patients and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Physicians are advised to discuss the following issues with patients for whom they prescribe [Drug Name] and to ask them to alert their physician if these occur:
Clinical Worsening and Suicide Risk: Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's physician, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
[This section will include either (1) a general statement for drugs for which pediatric data have not been submitted to FDA, as follows: "Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS -- Clinical Worsening and Suicide Risk)," or (2) more specific language regarding pediatric efficacy data that have been evaluated by FDA.]
Anyone considering the use of [Drug Name] in a child or adolescent must balance the potential risks with the clinical need.
These labeling revisions should be submitted in the form of a "Supplement - Changes Being Effected" within 30 days from the date of this letter.
Additionally, please be advised that we will also be requesting a Medication Guide in the format as outlined under 21 CFR 208 for all drugs in this therapeutic class. This Medication Guide would replace, if applicable, any patient package insert. We would also require that your product be distributed in unit-of-use packaging to ensure that every patient receives the Medication Guide. Additional information pertaining to the specifics of this Medication Guide will be forthcoming in the next 2-3 weeks.
If you have any questions, call Paul David, R.Ph., Senior Regulatory Project Manager, at (301) 594-5530.
Russell Katz, M.D.