Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its
pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma
concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly
through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.
Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although 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
such behaviors has not been established. Nevertheless, patients being treated with
antidepressants should be observed closely for clinical worsening and suicidality, especially
at the beginning of a course of drug therapy, or at the time of dose changes, either increases
or decreases. Consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients whose depression is persistently worse or
whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting
symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other
psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients
with major depressive disorder should be observed when treating patients with other psychiatric
and nonpsychiatric disorders.
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, consideration
should be given to changing the therapeutic regimen, including possibly discontinuing the
medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of
the patient’s presenting symptoms.
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, and
the other symptoms described above, as well as the emergence of suicidality, and to report
such symptoms immediately to health care providers. Prescriptions for Cymbalta should be
written for the smallest quantity of capsules consistent with good patient management, in order to
reduce the risk of overdose.
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.
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. It should be noted that Cymbalta is not approved for use in
treating bipolar depression.
Monoamine Oxidase Inhibitors (MAOI) — In patients receiving a serotonin reuptake
inhibitor in combination with a monoamine oxidase inhibitor, there have been reports of
serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma. These reactions have also been
reported in patients who have recently discontinued serotonin reuptake inhibitors and are
then started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. The effects of combined use of duloxetine and MAOIs have not been
evaluated in humans or animals. Therefore, because duloxetine is an inhibitor of both
serotonin and norepinephrine reuptake, it is recommended that duloxetine not be used in
combination with an MAOI, or within at least 14 days of discontinuing treatment with an
MAOI. Based on the half-life of duloxetine, at least 5 days should be allowed after stopping
duloxetine before starting an MAOI.