Revisions to product labeling

Revisions to Product Labeling
[These changes should be made to the box warning at the beginning of the package insert.]
DRUG NAME

Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term
studies of major depressive disorder (MDD) and other psychiatric disorders.
Anyone considering the use of [Insert established name] or any other antidepressant
in a child, adolescent, or young adult must balance this risk with the clinical need.
Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction
in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with
increases in the risk of suicide. Patients of all ages who are started on
antidepressant therapy should be monitored appropriately and 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. [Insert Drug Name] is not approved for use in pediatric
patients. [The previous sentence would be replaced with the sentence, below, for the
following drugs: Prozac: Prozac is approved for use in pediatric patients with MDD
and obsessive compulsive disorder (OCD). Zoloft: Zoloft is not approved for use in
pediatric patients except for patients with obsessive compulsive disorder (OCD).
Fluvoxamine: Fluvoxamine is not approved for use in pediatric patients except for
patients with obsessive compulsive disorder (OCD).] (See Warnings: Clinical
Worsening and Suicide Risk, Precautions: Information for Patients, and
Precautions: Pediatric Use)

[The following changes should be made to 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.
Suicide is a known risk of depression and certain other psychiatric disorders, and these
disorders themselves are the strongest predictors of suicide. There has been a long-
standing concern, however, that antidepressants may have a role in inducing worsening of
depression and the emergence of suicidality in certain patients during the early phases of
treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs
(SSRIs and others) showed that these drugs increase the risk of suicidal thinking and
behavior (suicidality) in children,adolescents, and young adults (ages 18-24) with major
depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not
show an increase in the risk of suicidality with antidepressants compared to placebo in
adults beyond age 24; there was a reduction with antidepressants compared to placebo in
adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD,
obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of
24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses
of placebo-controlled trials in adults with MDD or other psychiatric disorders included a
total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in
over 77,000 patients. There was considerable variation in risk of suicidality among
drugs, but a tendency toward an increase in the younger patients for almost all drugs
studied. There were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences (drug vs placebo),
however, were relatively stable within age strata and across indications. These risk
differences (drug-placebo difference in the number of cases of suicidality per 1000
patients treated) are provided in Table [add table number].

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled maintenance
trials in adults with depression that the use of antidepressants can delay the recurrence of
depression.
All patients being treated with antidepressants for any indication should be
monitored appropriately and 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.

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. [The labeling for the following drugs with discontinuation language would include the next paragraph: Celexa, Cymbalta, Effexor, Fluvoxamine, Lexapro, Paxil, Pexeva, Prozac, Sarafem, Symbyax, and Zoloft.] 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 [Insert established name], for
a description of the risks of discontinuation of [Insert established name]).

Families and caregivers of 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 [Insert Drug Name] should be written for the smallest
quantity of tablets consistent with good patient management, in order to reduce the risk of
overdose.

Screening Patients for Bipolar Disorder: 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 with
depressive symptoms 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. It should be noted that [Insert
Drug Name] is not approved for use in treating bipolar depression. [The previous
sentence would be replaced for the following drugs: Seroquel: It should be noted that
Seroquel is approved for use in treating adult bipolar depression. Symbyax: It should be noted that Symbyax is approved for use in treating adult bipolar depression. [The following changes should be made in current language under the
PRECAUTIONS-Information for Patients section.]

PRECAUTIONS-Information for Patients

Prescribers or other health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment with [Insert Drug Name]
and should counsel them in its appropriate use. A patient Medication Guide about
“Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal
Thoughts or Actions” is available for [Insert Drug Name]. The prescriber or health
professional should instruct patients, their families, 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.
Patients should be advised of the following issues and asked to alert their prescriber if
these occur while taking [Insert Drug Name].
Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers
should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), 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 look 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 prescriber or health
professional, 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.

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