Labeling Change
Request Letter for Antidepressant Medications
NDA XX-XXX
Dear :
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]
DRUG NAME
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.
Pediatric Use
[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.
|
Sincerely,
Russell Katz, M.D.
Director
Division of Neuropharmacological Drug Products
Office of Drug Evaluation
I
Center for Drug Evaluation and Research
|
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Date created: October 15, 2004, Updated, October
28, 2004 |