A brief synopsis on:

CYMBALTA®
(duloxetine hydrochloride) Delayed-release Capsules



DESCRIPTION
Cymbalta® (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake
inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-
naphthyloxy)-2-thiophenepropylamine hydrochloride.  

Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble
in water.
Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine
hydrochloride equivalent to 20, 30, or 60 mg of duloxetine, respectively. These enteric-coated
pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.
Inactive ingredients include FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl
methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium
dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow.

CLINICAL PHARMACOLOGY

Pharmacodynamics
Although the exact mechanisms of the antidepressant and central pain inhibitory action of
duloxetine in humans are unknown, the antidepressant and pain inhibitory actions are believed to
be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical
studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine
reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity
for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors
in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes
extensive metabolism, but the major circulating metabolites have not been shown to contribute
significantly to the pharmacologic activity of duloxetine.

Pharmacokinetics

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.  

CONTRAINDICATIONS

Hypersensitivity
Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of
the inactive ingredients.
Monoamine Oxidase Inhibitors
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated

Uncontrolled Narrow-Angle Glaucoma
In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its
use should be avoided in patients with uncontrolled narrow-angle glaucoma.

The following symptoms - SIDE EFFECTS

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.

Discontinuing Cymbalta, for a description of the risks of discontinuation of Cymbalta).
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.
Because Cymbalta is an inhibitor of both
serotonin and norepinephrine reuptake, it is recommended that Cymbalta 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 Cymbalta, at least 5 days should be allowed after stopping
Cymbalta before starting an MAOI.

PRECAUTIONS

General
Hepatotoxicity ” Cymbalta increases the risk of elevation of serum transaminase levels. . Because it is possible that
duloxetine and alcohol may interact to cause liver injury, Cymbalta should ordinarily not be
prescribed to patients with substantial alcohol use.
Effect on Blood Pressure ” In MDD clinical trials, Cymbalta treatment was associated with
mean increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic and an
increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg
compared to placebo.
Blood pressure should be measured prior to initiating treatment and periodically measured
throughout treatment

Activation of Mania/Hypomania ” In placebo-controlled trials in patients with major
depressive disorder, activation of mania or hypomania was reported in 0.1% (1/1139) of
Cymbalta-treated patients and 0.1% (1/777) of placebo-treated patients. Activation of
mania/hypomania has been reported in a small proportion of patients with mood disorders who
were treated with other marketed drugs effective in the treatment of major depressive disorder.
As with these other agents, Cymbalta should be used cautiously in patients with a history of
mania.

Seizures ” Cymbalta has not been systematically evaluated in patients with a seizure disorder,
and such patients were excluded from clinical studies. In placebo-controlled clinical trials in
patients with major depressive disorder, seizures occurred in 0.1% (1/1139) of patients treated
with Cymbalta and 0% (0/777) of patients treated with placebo. In placebo-controlled clinical
trials in patients with diabetic peripheral neuropathy, seizures did not occur in any patients
treated with either Cymbalta or placebo. Cymbalta should be prescribed with care in patients
with a history of a seizure disorder.
Controlled Narrow-Angle Glaucoma ” In clinical trials, Cymbalta was associated with an
increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled
narrow-angle glaucoma (see CONTRAINDICATIONS, Uncontrolled Narrow-Angle Glaucoma).

Discontinuing Cymbalta
Patients should be monitored for these symptoms when discontinuing treatment with Cymbalta.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been
reported . Patients should be monitored for these symptoms below when discontinuing treatment.

Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric
shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia,
hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have
been reported to be severe.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

MAOI's
Switching Patients to or from a Monoamine Oxidase Inhibitor
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy
with Cymbalta. In addition, at least 5 days should be allowed after stopping Cymbalta before
starting an MAOI

DOSAGE AND ADMINISTRATION
Initial Treatment

Major Depressive Disorder
Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg BID) to
60 mg/day (given either once a day or as 30 mg BID) without regard to meals.
There is no evidence that doses greater than 60 mg/day confer any additional benefits.

Diabetic Peripheral Neuropathic Pain
Cymbalta should be administered at a total dose of 60 mg/day given once a day, without regard
to meals.
While a 120 mg/day dose was shown to be safe and effective, there is no evidence that doses
higher than 60 mg confer additional significant benefit, and the higher dose is clearly less well
tolerated. For patients for whom tolerability is a concern, a lower starting dose may be
considered. Since diabetes is frequently complicated by renal disease, a lower starting dose and
gradual increase in dose should be considered for patients with renal impairment .

Maintenance/Continuation/Extended Treatment

Major Depressive Disorder
It is generally agreed that acute episodes of major depression require several months or longer
of sustained pharmacologic therapy. There is insufficient evidence available to answer the question of how long a patient should continue to be treated with Cymbalta.
Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose
for such treatment.

Diabetic Peripheral Neuropathic Pain
As the progression of diabetic peripheral neuropathy is highly variable and management of pain
is empirical, the effectiveness of Cymbalta must be assessed individually. Efficacy beyond
12 weeks has not been systematically studied in placebo-controlled trials, but a one-year
open-label safety study was conducted.

Dosage for Renally Impaired Patients ” Cymbalta is not recommended for patients with
end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine
clearance <30 mL/min) (see CLINICAL PHARMACOLOGY).

Dosage for Hepatically Impaired Patients ” It is recommended that Cymbalta not be
administered to patients with any hepatic insufficiency.  
Dosage for Elderly Patients ” No dose adjustment is recommended for elderly patients on the
basis of age. As with any drug, caution should be exercised in treating the elderly. When
individualizing the dosage in elderly patients, extra care should be taken when increasing the
dose.

PREGNANCY
Treatment of Pregnant Women During the Third Trimester ” Neonates exposed to SSRIs or
SNRIs, late in the third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding . When treating Pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cymbalta in the third trimester.

Labor and Delivery
The effect of duloxetine on labor and
used during labor and delivery only if the

Nursing Mothers
Duloxetine and/or its metabolites are
whether or not duloxetine and/or its metabolites
on Cymbalta is not recommended..


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Literature revised September 3, 2004
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.Cymbalta.com
PV 3601 AMP PRINTED IN USA
Copyright © 2004, Eli Lilly and Company. All rights reserved.