Patients should be advised to notify their physician if they
Patients should be advised to notify their physician if they
become pregnant during therapy
intend to become pregnant during therapy
are breast feeding [see Dosage and Administration (2.3) and Use in Specific Populations (8.1, 8.2, and 8.3)].
IMPRINT: LILLY 3237 60 MG
SHAPE: capsule
Boxed Warning
Boxed Warning Section
WARNING: SUICIDALITY AND ANTIDEPRESSANT
DRUGSAntidepressants 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 Cymbalta 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. Cymbalta is not approved for
use in pediatric patients. [see Warnings and
Precautions (5.1), Use in Specific Populations (8.4), and Information for Patients (17.2).]
WARNING: Suicidality and Antidepressant
DrugsSee full prescribing information for complete boxed
warning.
Increased risk of suicidal thinking and behavior in
children, adolescents, and young adults taking antidepressants for major
depressive disorder (MDD) and other psychiatric disorders. Cymbalta is not
approved for use in pediatric patients (5.1).
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 Cymbalta 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. Cymbalta is not approved for
use in pediatric patients. [see Warnings and
Precautions (5.1), Use in Specific Populations (8.4), and Information for Patients (17.2).]
WARNING: Suicidality and Antidepressant
Drugs
See full prescribing information for complete boxed
warning.
Increased risk of suicidal thinking and behavior in
children, adolescents, and young adults taking antidepressants for major
depressive disorder (MDD) and other psychiatric disorders. Cymbalta is not
approved for use in pediatric patients (5.1).
Recent Major Changes Section
Enter section text here
Indications and Usage, Generalized Anxiety Disorder (1.2) 11/2009
Dosage and Administration, Maintenance/Continuation/Extended Treatment (2.2) 11/2009
Warnings and Precautions, Serotonin Syndrome or Neuroleptic Malignant
Syndrome (NMS)-like Reactions (5.4)
01/2009
1 Indications And Usage
1.1 Major Depressive Disorder Cymbalta is indicated for the treatment of major depressive
disorder (MDD). The efficacy of Cymbalta was established in four short term and
one maintenance trial in adults [see Clinical Studies (14.1)].
A major depressive episode (DSM-IV) implies a prominent and relatively
persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood
that usually interferes with daily functioning, and includes at least 5 of the
following 9 symptoms: depressed mood, loss of interest in usual activities,
significant change in weight and/or appetite, insomnia or hypersomnia,
psychomotor agitation or retardation, increased fatigue, feelings of guilt or
worthlessness, slowed thinking or impaired concentration, or a suicide attempt
or suicidal ideation. 1.2 Generalized Anxiety Disorder Cymbalta is indicated
for the treatment of generalized anxiety disorder (GAD). The efficacy of
Cymbalta was established in three short-term trials and one maintenance trial in
adults [see Clinical Studies (14.2)].
Generalized anxiety disorder is
defined by the DSM-IV as excessive anxiety and worry, present more days than
not, for at least 6 months. The excessive anxiety and worry must be difficult to
control and must cause significant distress or impairment in normal functioning.
It must be associated with at least 3 of the following 6 symptoms: restlessness
or feeling keyed up or on edge, being easily fatigued, difficulty concentrating
or mind going blank, irritability, muscle tension, and/or sleep
disturbance. 1.3 Diabetic Peripheral Neuropathic Pain Cymbalta is indicated for the management of neuropathic pain
(DPNP) associated with diabetic peripheral neuropathy [see
Clinical Studies (14.3)]. 1.4 Fibromyalgia Cymbalta is indicated for the management of fibromyalgia (FM)
[see Clinical Studies (14.4)].
Cymbalta® is a serotonin and
norepinephrine reuptake inhibitor (SNRI) indicated for:
Major Depressive Disorder (MDD) (1.1)Efficacy was
established in 4 short-term and one maintenance trial in adults (14.1).
Generalized Anxiety Disorder (GAD) (1.2)Efficacy was
established in 3 short-term and one maintenance trial in adults (14.2).
Diabetic Peripheral Neuropathic Pain (DPNP) (1.3)
Fibromyalgia (FM) (1.4)
2 Dosage And Administration
Cymbalta should be swallowed whole and should not be chewed or
crushed, nor should the capsule be opened and its contents sprinkled on food or
mixed with liquids. All of these might affect the enteric coating. Cymbalta
should be given without regard to meals. 2.1 Initial Treatment Major Depressive Disorder — Cymbalta
should be administered at a total dose of 40 mg/day (given as 20 mg twice daily)
to 60 mg/day (given either once daily or as 30 mg twice daily). For some
patients, it may be desirable to start at 30 mg once daily for 1 week, to allow
patients to adjust to the medication before increasing to 60 mg once daily.
While a 120 mg/day dose was shown to be effective, there is no evidence that
doses greater than 60 mg/day confer any additional benefits. The safety of doses
above 120 mg/day has not been adequately evaluated [see
Clinical Studies (14.1)]. Generalized Anxiety Disorder — For
most patients, the recommended starting dose for Cymbalta is 60 mg administered
once daily. For some patients, it may be desirable to start at 30 mg once daily
for 1 week, to allow patients to adjust to the medication before increasing to
60 mg once daily. While a 120 mg once daily dose was shown to be effective,
there is no evidence that doses greater than 60 mg/day confer additional
benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg
once daily, dose increases should be in increments of 30 mg once daily. The
safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies (14.2)]. Diabetic Peripheral Neuropathic Pain
— The recommended dose for Cymbalta is 60 mg administered once daily. There is
no evidence that doses higher than 60 mg confer additional significant benefit
and the higher dose is clearly less well tolerated [see
Clinical Studies (14.3)]. 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 [see Clinical Pharmacology (12.3) and Dosage and Administration (2.3)]. Fibromyalgia — The recommended dose
for Cymbalta is 60 mg administered once daily. Treatment should begin at 30 mg
once daily for 1 week, to allow patients to adjust to the medication before
increasing to 60 mg once daily. Some patients may respond to the starting dose.
There is no evidence that doses greater than 60 mg/day confer additional
benefit, even in patients who do not respond to a 60 mg dose, and higher doses
are associated with a higher rate of adverse reactions [see
Clinical Studies (14.4)]. 2.2 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. Maintenance of efficacy in MDD was demonstrated with
Cymbalta as monotherapy. Cymbalta should be administered at a total dose of
60 mg once daily. Patients should be periodically reassessed to determine the
need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)]. Generalized Anxiety Disorder — It is generally agreed
that episodes of generalized anxiety disorder require several months or longer
of sustained pharmacological therapy. Maintenance of efficacy in GAD was
demonstrated with Cymbalta as monotherapy. Cymbalta should be administered in a
dose range of 60-120 mg once daily. Patients should be periodically reassessed
to determine the continued need for maintenance treatment and the appropriate
dose for such treatment [see Clinical Studies (14.2)]. 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. Fibromyalgia — Fibromyalgia is recognized as a chronic
condition. The efficacy of Cymbalta in the management of fibromyalgia has been
demonstrated in placebo-controlled studies up to 3 months. The efficacy of
Cymbalta was not demonstrated in longer studies; however, continued treatment
should be based on individual patient response. 2.3 Dosing in Special Populations Hepatic Insufficiency — It is
recommended that Cymbalta should ordinarily not be administered to patients with
any hepatic insufficiency [see Warnings and Precautions (5.12) and Use in Specific Populations (8.9)]. Severe Renal Impairment — Cymbalta
is not recommended for patients with end-stage renal disease or severe renal
impairment (estimated creatinine clearance less than 30 mL/min) [see Warnings and Precautions (5.12) and Use in
Specific Populations (8.10)]. 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 [see Use in Specific Populations (8.5)]. Pregnant Women — There are no
adequate and well-controlled studies in pregnant women; therefore, Cymbalta
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus [see Use in Specific Populations
(8.1)]. Nursing Mothers — Because the safety
of duloxetine in infants is not known, nursing while on Cymbalta is not
recommended [see Use in Specific Populations (8.3)]. 2.4 Discontinuing Cymbalta Symptoms associated with discontinuation of Cymbalta and other
SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than
abrupt cessation is recommended whenever possible [see
Warnings and Precautions (5.6)]. 2.5 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 [see
Contraindications (4.1) and Warnings and Precautions (5.4)].
Cymbalta should generally be administered once daily without regard to
meals. Cymbalta should be swallowed whole and should not be chewed or crushed,
nor should the capsule be opened and its contents be sprinkled on food or mixed
with liquids (2.1).
Indication
Starting
Dose
Target Dose
Maximum
Dose
MDD (2.1, 2.2)
40 mg/day to 60 mg/day
Acute Treatment: 40 mg/day (20 mg
twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance
Treatment: 60 mg/day
120 mg/day
GAD (2.1)
60 mg/day
60 mg/day (once daily)
120 mg/day
DPNP (2.1)
60 mg/day
60 mg/day (once daily)
60 mg/day
FM (2.1)
30 mg/day
60 mg/day (once daily)
60 mg/day
Some patients may benefit from starting at 30 mg once daily.
There is no evidence that doses greater than 60 mg/day confers additional
benefit, while some adverse reactions were observed to be dose-dependent.
Discontinuing Cymbalta: A gradual dose reduction is recommended to avoid
discontinuation symptoms (5.6).
3 Dosage Forms And Strengths
Cymbalta is available as delayed release capsules: 20mg opaque green capsules imprinted with “Lilly 3235 20mg” 30mg opaque white and blue capsules imprinted with “Lilly 3240 30mg” 60mg opaque green and blue capsules imprinted with “Lilly 3237 60mg” 60mg opaque green and blue capsules imprinted with “Lilly 3270 60mg”
20 mg, 30 mg, and 60 mg capsules (3)
4 Contraindications
4.1 Monoamine Oxidase Inhibitors Concomitant use in patients taking monoamine oxidase inhibitors
(MAOIs) is contraindicated due to the risk of serious, sometimes fatal, drug
interactions with serotonergic drugs. These interactions may include
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 [see Dosage and
Administration (2.5) and Warnings and Precautions (5.4)]. 4.2 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 [see Warnings and
Precautions (5.12)].
Use of a monoamine oxidase inhibitor concomitantly or in close temporal
proximity (4.1)
Use in patients with uncontrolled narrow-angle glaucoma (4.2)
5 Warnings And Precautions
5.1 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 of 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 1.
Age Range
Drug-Placebo Difference in Number of Cases of Suicidality per 1000Patients Treated
Increases Compared to Placebo
less than 18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
greater than or equal to 65
6 fewer cases
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.
If the decision has been made to discontinue treatment, medication should be
tapered, as rapidly as is feasible, but with recognition that discontinuation
can be associated with certain symptoms [see Dosage and
Administration (2.4) and Warnings and Precautions (5.6) for descriptions of the risks of discontinuation of
Cymbalta].
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 Cymbalta should be written for the smallest quantity of
capsules 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 Cymbalta (duloxetine)
is not approved for use in treating bipolar depression. 5.2 Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in
patients treated with Cymbalta. These cases have presented as hepatitis with
abdominal pain, hepatomegaly, and elevation of transaminase levels to more than
twenty times the upper limit of normal with or without jaundice, reflecting a
mixed or hepatocellular pattern of liver injury. Cymbalta should be discontinued
in patients who develop jaundice or other evidence of clinically significant
liver dysfunction and should not be resumed unless another cause can be
established.
Cases of cholestatic jaundice with minimal elevation of transaminase levels
have also been reported. Other postmarketing reports indicate that elevated
transaminases, bilirubin, and alkaline phosphatase have occurred in patients
with chronic liver disease or cirrhosis.
Cymbalta increased the risk of elevation of serum transaminase levels in
development program clinical trials. Liver transaminase elevations resulted in
the discontinuation of 0.3% (82/27,229) of Cymbalta-treated patients. In these
patients, the median time to detection of the transaminase elevation was about
two months. In placebo-controlled trials in any indication, elevation of ALT
greater than 3 times the upper limit of normal occurred in 1.1% (85/7,632) of
Cymbalta-treated patients compared to 0.2% (13/5,578) of placebo-treated
patients. In placebo-controlled studies using a fixed dose design, there was
evidence of a dose response relationship for ALT and AST elevation of greater than 3
times the upper limit of normal and greater than 5 times the upper limit of normal,
respectively.
Because it is possible that duloxetine and alcohol may interact to cause
liver injury or that duloxetine may aggravate pre-existing liver disease,
Cymbalta should ordinarily not be prescribed to patients with substantial
alcohol use or evidence of chronic liver disease. 5.3 Orthostatic Hypotension and Syncope Orthostatic hypotension and syncope have been reported with
therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to
occur within the first week of therapy but can occur at any time during
duloxetine treatment, particularly after dose increases. The risk of blood
pressure decreases may be greater in patients taking concomitant medications
that induce orthostatic hypotension (such as antihypertensives) or are potent
CYP1A2 inhibitors [see Warnings and Precautions (5.10) and Drug Interactions (7.1)] and
in patients taking duloxetine at doses above 60 mg daily. Consideration should
be given to discontinuing duloxetine in patients who experience symptomatic
orthostatic hypotension and/or syncope during duloxetine therapy. 5.4 Serotonin Syndrome or Neuroleptic Malignant
Syndrome (NMS)-like Reactions The development of a
potentially life-threatening serotonin syndrome or Neuroleptic Malignant
Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone,
including Cymbalta treatment, but particularly with concomitant use of
serotonergic drugs (including triptans) with drugs which impair metabolism of
serotonin (including MAOIs), or with antipsychotics or other dopamine
antagonists. Serotonin syndrome symptoms may include mental status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g.,
nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can
resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle
rigidity, autonomic instability with possible rapid fluctuation of vital signs,
and mental status changes. Patients should be monitored for the emergence of
serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of Cymbalta
with MAOIs intended to treat depression is contraindicated [see Contraindications (4.1)].
If concomitant treatment of
Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically
warranted, careful observation of the patient is advised, particularly during
treatment initiation and dose increases [see Drug
Interactions (7.15)].
The concomitant use of Cymbalta
with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.14)].
Treatment with duloxetine and any
concomitant serotonergic or antidopaminergic agents, including antipsychotics,
should be discontinued immediately if the above events occur and supportive
symptomatic treatment should be initiated. 5.5 Abnormal Bleeding SSRIs and SNRIs, including duloxetine, may increase the risk of
bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs, warfarin, and other anti-coagulants may add to this risk. Case reports
and epidemiological studies (case-control and cohort design) have demonstrated
an association between use of drugs that interfere with serotonin reuptake and
the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs
and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae
to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the
concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect
coagulation. 5.6 Discontinuation of Treatment with Cymbalta Discontinuation symptoms have been systematically evaluated in
patients taking duloxetine. Following abrupt or tapered discontinuation in
placebo-controlled clinical trials, the following symptoms occurred at a rate
greater than or equal to 1% and at a significantly higher rate in
duloxetine-treated patients compared to those discontinuing from placebo:
dizziness, nausea, headache, fatigue, paresthesia, vomiting, irritability,
nightmares, insomnia, diarrhea, anxiety, hyperhidrosis and vertigo.
During marketing of other SSRIs and SNRIs (serotonin and norepinephrine
reuptake inhibitors), there have been spontaneous reports of adverse events
occurring upon discontinuation of these drugs, particularly when abrupt,
including the following: 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.
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. 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 [see
Dosage and Administration (2.4)]. 5.7 Activation of Mania/Hypomania In placebo-controlled trials in patients with major depressive
disorder, activation of mania or hypomania was reported in 0.1% (2/2,489) of
duloxetine-treated patients and 0.1% (1/1,625) of placebo-treated patients. No
activation of mania or hypomania was reported in DPNP, GAD, or fibromyalgia
placebo-controlled trials. Activation of mania or 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. 5.8 Seizures Duloxetine has not been systematically evaluated in patients with
a seizure disorder, and such patients were excluded from clinical studies. In
placebo-controlled clinical trials, seizures/convulsions occurred in
0.03% (3/9,445) of patients treated with duloxetine and 0.01% (1/6,770) of
patients treated with placebo. Cymbalta should be prescribed with care in
patients with a history of a seizure disorder. 5.9 Effect on Blood Pressure In clinical trials across indications, relative to placebo,
duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in
systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There
was no significant difference in the frequency of sustained (3 consecutive
visits) elevated blood pressure. In a clinical pharmacology study designed to
evaluate the effects of duloxetine on various parameters, including blood
pressure at supratherapeutic doses with an accelerated dose titration, there was
evidence of increases in supine blood pressure at doses up to 200 mg twice
daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate
was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg
(systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.
Blood pressure should be measured prior to initiating treatment and
periodically measured throughout treatment [see Adverse
Reactions (6.7)]. 5.10 Clinically Important Drug Interactions Both CYP1A2 and CYP2D6 are responsible for duloxetine
metabolism. Potential for Other Drugs to Affect
Cymbalta
CYP1A2 Inhibitors — Co-administration of Cymbalta
with potent CYP1A2 inhibitors should be avoided [see Drug
Interactions (7.1)].
CYP2D6 Inhibitors — Because CYP2D6 is involved in
duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of
CYP2D6 would be expected to, and does, result in higher concentrations (on
average of 60%) of duloxetine [see Drug Interactions (7.2)]. Potential for Cymbalta to Affect Other
Drugs
Drugs Metabolized by CYP2D6 — Co-administration of
Cymbalta with drugs that are extensively metabolized by CYP2D6 and that have a
narrow therapeutic index, including certain antidepressants (tricyclic
antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine),
phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide),
should be approached with caution. Plasma TCA concentrations may need to be
monitored and the dose of the TCA may need to be reduced if a TCA is
co-administered with Cymbalta. Because of the risk of serious ventricular
arrhythmias and sudden death potentially associated with elevated plasma levels
of thioridazine, Cymbalta and thioridazine should not be co-administered [see Drug Interactions (7.9)]. Other Clinically Important Drug
Interactions
Alcohol — Use of Cymbalta concomitantly with heavy
alcohol intake may be associated with severe liver injury. For this reason,
Cymbalta should ordinarily not be prescribed for patients with substantial
alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.16)].
CNS Acting Drugs — Given the primary CNS effects
of Cymbalta, it should be used with caution when it is taken in combination with
or substituted for other centrally acting drugs, including those with a similar
mechanism of action [see Warnings and Precautions (5.10) and Drug Interactions (7.17)]. 5.11 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and
SNRIs, including Cymbalta. In many cases, this hyponatremia appears to be the
result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Cases with serum sodium lower than 110 mmol/L have been reported and appeared to
be reversible when Cymbalta was discontinued. Elderly patients may be at greater
risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking
diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)].
Discontinuation of Cymbalta should be considered in patients with symptomatic
hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty
concentrating, memory impairment, confusion, weakness, and unsteadiness, which
may lead to falls. More severe and/or acute cases have been associated with
hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.12 Use in Patients with Concomitant Illness Clinical experience with Cymbalta in patients with concomitant
systemic illnesses is limited. There is no information on the effect that
alterations in gastric motility may have on the stability of Cymbalta's enteric
coating. In extremely acidic conditions, Cymbalta, unprotected by the enteric
coating, may undergo hydrolysis to form naphthol. Caution is advised in using
Cymbalta in patients with conditions that may slow gastric emptying (e.g., some
diabetics).
Cymbalta has not been systematically evaluated in patients with a recent
history of myocardial infarction or unstable coronary artery disease. Patients
with these diagnoses were generally excluded from clinical studies during the
product's premarketing testing. Hepatic Insufficiency — Cymbalta
should ordinarily not be used in patients with hepatic insufficiency [see Dosage and Administration (2.3), Warnings
and Precautions (5.2), and Use in Specific Populations (8.9)]. Severe Renal Impairment — Cymbalta
should ordinarily not be used in patients with end-stage renal disease or severe
renal impairment (creatinine clearance less than 30 mL/min). Increased plasma
concentration of duloxetine, and especially of its metabolites, occur in
patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.3) and Use in
Specific Populations (8.10)]. 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 (4.2)]. Glycemic Control in Patients with
Diabetes — As observed in DPNP trials, Cymbalta treatment worsens
glycemic control in some patients with diabetes. In three clinical trials of
Cymbalta for the management of neuropathic pain associated with diabetic
peripheral neuropathy, the mean duration of diabetes was approximately 12 years,
the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline
hemoglobin A1c (HbA1c) was 7.8%.
In the 12-week acute treatment phase of these studies, Cymbalta was associated
with a small increase in mean fasting blood glucose as compared to placebo. In
the extension phase of these studies, which lasted up to 52 weeks, mean fasting
blood glucose increased by 12 mg/dL in the Cymbalta group and decreased by 11.5
mg/dL in the routine care group. HbA1c increased by 0.5%
in the Cymbalta and by 0.2% in the routine care groups. 5.13 Urinary Hesitation and Retention Cymbalta is in a class of drugs known to affect urethral
resistance. If symptoms of urinary hesitation develop during treatment with
Cymbalta, consideration should be given to the possibility that they might be
drug-related.
In post marketing experience, cases of urinary retention have been observed.
In some instances of urinary retention associated with duloxetine use,
hospitalization and/or catheterization has been needed. 5.14 Laboratory Tests No specific laboratory tests are recommended.
Suicidality: Monitor for clinical worsening and suicide risk (5.1).
Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in
patients treated with Cymbalta. Cymbalta should be discontinued in patients who
develop jaundice or other evidence of clinically significant liver dysfunction
and should not be resumed unless another cause can be established. Cymbalta
should ordinarily not be prescribed to patients with substantial alcohol use or
evidence of chronic liver disease (5.2).
Orthostatic Hypotension and Syncope: Cases have been reported with
duloxetine therapy (5.3).
Serotonin Syndrome, or Neuroleptic Malignant Syndrome (NMS)-like reactions:
Serotonin syndrome or NMS-like reactions have been reported with SSRIs and
SNRIs. Discontinue Cymbalta and initiate supportive treatment (5.4, 7.14).
Abnormal Bleeding: Cymbalta may increase the risk of bleeding events.
Patients should be cautioned about the risk of bleeding associated with the
concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect
coagulation (5.5, 7.4).
Discontinuation: May result in symptoms, including dizziness, nausea,
headache, fatigue, paresthesia, vomiting, irritability, nightmares, insomnia,
diarrhea, anxiety, hyperhidrosis, and vertigo (5.6).
Activation of mania or hypomania has occurred (5.7).
Seizures: Prescribe with care in patients with a history of seizure disorder
(5.8).
Blood Pressure: Monitor blood pressure prior to initiating treatment and
periodically throughout treatment (5.9).
Inhibitors of CYP1A2 or Thioridazine: Should not administer with Cymbalta
(5.10).
Hyponatremia: Cases of hyponatremia have been reported (5.11).
Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not be
administered to these patients (5.12).
Controlled Narrow-Angle Glaucoma: Use cautiously in these patients (5.12).
Glucose Control in Diabetes: In diabetic peripheral neuropathic pain
patients, small increases in fasting blood glucose, HbA1c, and total cholesterol have been observed (5.12).
Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.12).
Urinary Hesitation and Retention (5.13).
6 Adverse Reactions
6.1 Clinical Trial Data Sources The data described below reflect exposure to duloxetine in
placebo-controlled trials for MDD (N=2,327), GAD (N=668), DPNP (N=568), and FM
(N=876). The population studied was 17 to 89 years of age; 64.8%, 64.7%, 38.7%,
and 94.6% female; and 85.5%, 84.6%, 77.6%, and 88% Caucasian for MDD, GAD, DPNP,
and FM, respectively. Most patients received doses of a total of 60 to 120 mg
per day [see Clinical Studies (14)].
The stated frequencies of adverse reactions represent the proportion of
individuals who experienced, at least once, a treatment-emergent adverse
reaction of the type uled. A reaction was considered treatment-emergent if it
occurred for the first time or worsened while receiving therapy following
baseline evaluation. Reactions reported during the studies were not necessarily
caused by the therapy, and the frequencies do not reflect investigator
impression (assessment) of causality.
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice. 6.2 Adverse Reactions Reported as Reasons for
Discontinuation of Treatment in Placebo-Controlled Trials Major Depressive Disorder —
Approximately 9% (209/2,327) of the patients who received duloxetine in
placebo-controlled trials for MDD discontinued treatment due to an adverse
reaction, compared with 4.7% (68/1,460) of the patients receiving placebo.
Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction
reported as a reason for discontinuation and considered to be drug-related
(i.e., discontinuation occurring in at least 1% of the duloxetine-treated
patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder —
Approximately 15.3% (102/668) of the patients who received duloxetine in
placebo-controlled trials for GAD discontinued treatment due to an adverse
reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions
reported as a reason for discontinuation and considered to be drug-related (as
defined above) included nausea (duloxetine 3.7%, placebo 0.2%), vomiting
(duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo
0.2%). Diabetic Peripheral Neuropathic Pain
— Approximately 14.3% (81/568) of the patients who received duloxetine in
placebo-controlled trials for DPNP discontinued treatment due to an adverse
reaction, compared with 7.2% (16/223) for placebo. Common adverse reactions
reported as a reason for discontinuation and considered to be drug-related (as
defined above) were nausea (duloxetine 3.5%, placebo 0.4%), dizziness
(duloxetine 1.6%, placebo 0.4%), somnolence (duloxetine 1.6%, placebo 0.0%), and
fatigue (duloxetine 1.1%, placebo 0.0%). Fibromyalgia — Approximately 19.5%
(171/876) of the patients who received duloxetine in 3 to 6 month
placebo-controlled trials for FM discontinued treatment due to an adverse
reaction, compared with 11.8% (63/535) for placebo. Common adverse reactions
reported as a reason for discontinuation and considered to be drug-related (as
defined above) included nausea (duloxetine 1.9%, placebo 0.7%), somnolence
(duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo
0.2%). 6.3 Adverse Reactions Occurring at an Incidence of 5%
or More and at least Twice Placebo Among Duloxetine-Treated Patients in
Placebo-Controlled Trials Pooled Trials for all Approved
Indications — The most commonly observed adverse reactions in
Cymbalta-treated patients (incidence of at least 5% and at least twice the
incidence in placebo patients) were nausea, dry mouth, constipation, somnolence,
hyperhidrosis, and decreased appetite.
In addition to the adverse reactions uled above, DPNP trials also included
dizziness and asthenia. 6.4 Adverse Reactions Occurring at an Incidence of 5%
or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Table 2 gives the incidence of
treatment-emergent adverse reactions in placebo-controlled trials for approved
indications that occurred in 5% or more of patients treated with duloxetine and
with an incidence greater than placebo.
Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More in Placebo-Controlled Trials of Approved Indications
Percentage of Patients
Reporting Reaction
Adverse Reaction
Cymbalta(N=4843)
Placebo(N=3048)
Nausea
25
9
Headache
16
15
Dry mouth
14
6
Fatigueb
11
6
Insomniaa,c
11
7
Dizziness
11
6
Somnolencea,d
11
3
Constipationa
11
4
Diarrhea
10
7
Decreased appetitea,e
8
2
Hyperhidrosis
7
2
a Events for which there was a significant dose-dependent relationship in fixed-dose
studies, excluding three MDD studies which did not have a placebo lead-in period
or dose titration.
b Also includes asthenia
c Also includes middle insomnia, early morning awakening, and initial insomnia
d Also includes hypersomnia and sedation
e Also includes anorexia
6.5 Adverse Reactions Occurring at an Incidence of 2%
or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse
reactions in MDD and GAD placebo-controlled trials for approved indications that
occurred in 2% or more of patients treated with duloxetine and with an incidence
greater than placebo.
Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in MDD and GAD Placebo-Controlled Trials
Percentage of Patients
Reporting Reaction
System Organ Class / Adverse Reaction
Cymbalta(N=2995)
Placebo(N=1955)
Cardiac Disorders
Palpitations
2
2
Eye Disorders
Vision blurred
3
2
Gastrointestinal Disorders
Nausea
25
9
Dry mouth
15
6
Diarrhea
10
7
Constipationa
10
4
Abdonimal painb
4
4
Vomiting
5
2
General Disorders and Administration Site Conditions
Fatiguec
10
6
Investigations
Weight decreaseda
2
less than 1
Metabolism and Nutrition Disorders
Decreased appetited
7
2
Nervous System Disorders
Dizziness
10
6
Somnolencee
10
4
Tremor
3
less than 1
Psychiatric Disorders
Insomniaf
10
6
Agitationg
5
3
Anxiety
3
2
Libido decreasedh
4
1
Orgasm abnormali
3
less than 1
Abnormal dreamsj
2
1
Reproductive System and Breast Disorders
Erectile dysfunctionk
5
1
Ejaculation delayeda,k
3
less than 1
Ejaculation disorderk,l
2
less than l
Respiratory, Thoracic, and Mediastinal Disorders
Yawning
2
less than 1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis
6
2
Vascular Disorders
Hot flush
2
less than 1
a Events for which there was a significant dose-dependent relationship in fixed-dose
studies, excluding three MDD studies which did not have a placebo lead-in period
or dose titration.
b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness,
abdominal discomfort, and gastrointestinal pain
c Also includes asthenia
d Also includes anorexia
e Also includes hypersomnia and sedation
f Also includes middle insomnia, early morning awakening, and initial insomnia
g Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor
agitation
h Also includes loss of libido
i Also includes anorgasmia
j Also includes nightmare
k Male patients only
l Also includes ejaculation failure and ejaculation dysfunction
Most common adverse reactions (≥5% and at least twice the incidence of
placebo patients): nausea, dry mouth, constipation, somnolence, hyperhidrosis,
and decreased appetite (6.3).
To report SUSPECTED ADVERSE REACTIONS, contact
Eli Lilly and Company at 1-800-LillyRx or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
Diabetic Peripheral Neuropathic Pain — Table 4 gives the incidence of treatment-emergent adverse events
that occurred in 2% or more of patients treated with Cymbalta in the
premarketing acute phase of DPNP placebo-controlled trials (doses of 20 to
120 mg/day) and with an incidence greater than placebo.
Table 4: Treatment-Emergent Adverse Reactions Incidence of 2% or More in DPNP Placebo-Controlled Trials
Percentage of Patients
Reporting Reaction
System Organ Class / Adverse Reaction
Cymbalta20 mg once daily(N=115)
Cymbalta60 mg once daily(N=228)
Cymbalta60 mg twice daily(N=225)
Placebo
(N=223)
Gastrointestinal Disorders
Nausea
14
22
30
9
Constipatioin
5
11
15
3
Diarrhea
13
11
7
6
Dry mouth
5
7
12
4
Vomiting
6
5
5
4
Dyspepsia
4
4
4
3
Loose stools
2
3
2
1
General Disorders and Administration Site Conditions
Fatigue
2
10
12
5
Asthenia
2
4
8
1
Pyrexia
2
1
3
1
Infections and Infestations
Nasopharyngitis
9
7
9
5
Metabolism and Nutrition Disorders
Decreased appetite
3
4
11
less than 1
Anorexia
3
3
5
less than 1
Musculoskeletal and Connective Tissue Disorders
Muscle cramp
5
4
4
3
Myalgia
3
1
4
less than 1
Nervous System Disorders
Somnolence
7
15
21
5
Headache
13
13
15
10
Dizziness
6
14
17
6
Tremor
0
1
5
0
Psychiatric Disorders
Insomnia
9
8
13
7
Renal and urinary Disorders
Pollakiuria
3
1
5
2
Reproductive System and Breast Disorders
Erectile dysfunctiona
0
1
4
0
Respiratory, Thoracic and Mediastinal Disorders
Cough
6
3
5
4
Pharyngolaryngeal pain
3
1
6
1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis
6
6
8
2
a Male patients only.
Fibromyalgia — Table 5 gives the
incidence of treatment-emergent adverse events that occurred in 2% or more of
patients treated with Cymbalta in the premarketing acute phase of FM
placebo-controlled trials and with an incidence greater than placebo.
Table 5: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in Fibromyalgia Placebo-Controlled Trials
Percentage of Patients
Reporting Reaction
System Organ Class / Adverse Reaction
Cymbalta(N=876)
Placebo(N=535)
Cardiac Disorders
Palpitations
2
2
Eye Disorders
Vision blurred
2
1
Gastrointestinal Disorders
Nausea
29
11
Dry mouth
18
5
Constipation
15
4
Diarrhea
12
8
Dyspepsia
5
3
General Disorders and Administration Site Conditions
Fatigueb
15
8
Immune System Disorders
Seasonal allergy
3
2
Infections and Infestations
Upper respiratory tract infection
7
6
Urinary tract infection
3
3
Influenza
2
2
Gastroenteritis viral
2
2
Investigations
Weight increased
2
1
Metabolism and Nutrition Disorders
Decreased appetitec
11
2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain
5
4
Muscle spasms
4
3
Nervous System Disorders
Headache
20
12
Dizziness
11
74
Somnolenced
11
3
Tremor
4
1
Paraesthesia
4
4
Migraine
3
3
Dysgeusia
3
1
Psychiatric Disorders
Insomniae
16
10
Agitationf
6
2
Sleep disorder
3
2
Abnormal dreamsg
3
1
Orgasm abnormalh
3
less than 1
Libido decreasedi
2
less than 1
Reproductive System and Breast Disorders
Ejaculation disordera,j
4
0
Penis disordera
2
0
Respiratory, Thoracic, and Mediastinal Disorders
Cough
4
3
Pharyngolaryngeal pain
3
3
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis
7
1
Rash
4
2
Pruritis
3
2
Vascular Disorders
Hot flush
3
2
a Male patients only (N = 46 duloxetine-treated patients versus 26 placebo patients)
b Also includes asthenia
c Also includes anorexia
d Also includes hypersomnia and sedation
e Also includes middle insomnia, early morning awakening, and initial insomnia
f Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor
agitation
g Also includes nightmare
h Also includes anorgasmia
i Also includes loss of libido
j Also includes ejaculation failure and ejaculation dysfunction
6.6 Effects on Male and Female Sexual Function Changes in sexual desire, sexual performance and sexual
satisfaction often occur as manifestations of psychiatric disorders or diabetes,
but they may also be a consequence of pharmacologic treatment. Because adverse
sexual reactions are presumed to be voluntarily underreported, the Arizona
Sexual Experience Scale (ASEX), a validated measure designed to identify sexual
side effects, was used prospectively in 4 MDD placebo-controlled trials. In
these trials, as shown in Table 6 below, patients treated with
Cymbalta experienced significantly more sexual dysfunction, as measured by the
total score on the ASEX, than did patients treated with placebo. Gender analysis
showed that this difference occurred only in males. Males treated with Cymbalta
experienced more difficulty with ability to reach orgasm (ASEX Item 4) than
males treated with placebo. Females did not experience more sexual dysfunction
on Cymbalta than on placebo as measured by ASEX total score. Negative numbers
signify an improvement from a baseline level of dysfunction, which is commonly
seen in depressed patients. Physicians should routinely inquire about possible
sexual side effects.
Table 6: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials
Male
Patientsa
Female
Patientsa
Cymbalta(n=175)
Placebo(n=83)
Cymbalta(n=241)
Placebo(n=126)
ASEX Total (Items 1-5)
0.56b
-1.07
-1.15
-1.07
Item 1 -- Sex drive
-0.07
-0.12
-0.32
-0.24
Item 2 -- Arousal
0.01
-0.26
-0.21
-0.18
Item 3 -- Ability to achieve errection (men); Lubrication(women)
0.03
-0.25
-0.17
-0.18
Item 4 -- Ease of reaching orgasm
0.40c
-0.24
-0.09
-0.13
Item 5 -- Orgasm satisfaction
0.09
-0.13
-0.11
-0.17
a n=Number of patients with non-missing change score for ASEX total
b p=0.013 versus placebo
c p less than 0.001 versus placebo
6.7 Vital Sign Changes In clinical trials across indications, relative to placebo,
duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in
systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There
was no significant difference in the frequency of sustained (3 consecutive
visits) elevated blood pressure [see Warnings and
Precautions (5.3 and 5.9)].
Duloxetine treatment, for up to 26 weeks in placebo-controlled trials
typically caused a small increase in heart rate compared to placebo of up to
3-4 beats per minute. 6.8 Weight Changes In placebo-controlled clinical trials, MDD and GAD patients
treated with Cymbalta for up to 10 weeks experienced a mean weight loss of
approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg
in placebo-treated patients. In DPN placebo-controlled clinical trials, patients
treated with Cymbalta for up to 13-weeks experienced a mean weight loss of
approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg
in placebo-treated patients. In fibromyalgia studies, patients treated with
Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.4
kg compared with a mean weight gain of approximately 0.3 kg in placebo-treated
patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine
patients had a mean weight increase of 0.7 kg. 6.9 Laboratory Changes Cymbalta treatment in placebo-controlled clinical trials, was
associated with small mean increases from baseline to endpoint in ALT, AST, CPK,
and alkaline phosphatase; infrequent, modest, transient, abnormal values were
observed for these analytes in Cymbalta-treated patients when compared with
placebo-treated patients [see Warnings and Precautions (5.2)]. 6.10 Electrocardiogram Changes Electrocardiograms were obtained from duloxetine-treated patients
and placebo-treated patients in clinical trials lasting up to 13 weeks. No
clinically significant differences were observed for QTc, QT, PR, and QRS
intervals between duloxetine-treated and placebo-treated patients. There were no
differences in clinically meaningful QTcF elevations between duloxetine and
placebo. In a positive-controlled study in healthy volunteers using duloxetine
up to 200 mg twice daily, no prolongation of the corrected QT interval was
observed. 6.11 Other Adverse Reactions Observed During the
Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Following is a ul of treatment-emergent adverse reactions
reported by patients treated with duloxetine in clinical trials. In clinical
trials of all indications, 27,229 patients were treated with duloxetine. Of
these, 29% (7,886) took duloxetine for at least 6 months, and 13.3% (3,614) for
at least one year. The following uling is not intended to include reactions
(1) already uled in previous tables or elsewhere in labeling, (2) for which a
drug cause was remote, (3) which were so general as to be uninformative,
(4) which were not considered to have significant clinical implications, or (5)
which occurred at a rate equal to or less than placebo.
Reactions are categorized by body system according to the following
definitions: frequent adverse reactions are those occurring in at least
1/100 patients; infrequent adverse reactions are those occurring in 1/100 to
1/1000 patients; rare reactions are those occurring in fewer than
1/1000 patients.
Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.
Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.
Gastrointestinal Disorders — Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, and
stomatitis; Rare: gastric ulcer, hematochezia, and
melena.
General Disorders and Administration Site Conditions
— Frequent: chills/rigors; Infrequent: feeling abnormal, feeling hot and/or cold,
malaise, and thirst; Rare: gait disturbance.
Infections and Infestations — Infrequent: gastroenteritis and laryngitis.
Skin and Subcutaneous Tissue Disorders —Infrequent: cold sweat, dermatitis contact, erythema,
increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.
Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and
peripheral coldness. 6.12 Postmarketing Spontaneous Reports The following adverse reactions have been identified during
postapproval use of Cymbalta. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug
exposure.
Adverse reactions reported since market introduction that were temporally
related to duloxetine therapy and not mentioned elsewhere in labeling
include: anaphylactic reaction, aggression and anger (particularly early in
treatment or after treatment discontinuation), angioneurotic edema, erythema
multiforme, extrapyramidal disorder, glaucoma, gynecological bleeding,
hallucinations, hyperglycemia, hypersensitivity, hypertensive crisis, muscle
spasm, rash, restless legs syndrome, seizures upon treatment discontinuation,
supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus,
and urticaria.
Serious skin reactions including Stevens-Johnson Syndrome that have required
drug discontinuation and/or hospitalization have been reported with duloxetine.
7 Drug Interactions
Both CYP1A2 and CYP2D6 are responsible for duloxetine
metabolism. 7.1 Inhibitors of CYP1A2 When duloxetine 60 mg was co-administered with fluvoxamine 100
mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was
increased approximately 6-fold, the Cmax was increased
about 2.5-fold, and duloxetine t1/2 was increased
approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include
cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions (5.10)]. 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine
(20 mg once daily) increased the concentration of duloxetine AUC by about 60%,
and greater degrees of inhibition are expected with higher doses of paroxetine.
Similar effects would be expected with other potent CYP2D6 inhibitors
(e.g., fluoxetine, quinidine) [see Warnings and Precautions
(5.10)]. 7.3 Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily with
fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer
subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax. 7.4 Drugs that Interfere with Hemostasis (e.g.,
NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in
hemostasis. Epidemiological studies of the case-control and cohort design that
have demonstrated an association between use of psychotropic drugs that
interfere with serotonin reuptake and the occurrence of upper gastrointestinal
bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including
increased bleeding, have been reported when SSRIs or SNRIs are coadministered
with warfarin. Patients receiving warfarin therapy should be carefully monitored
when duloxetine is initiated or discontinued [see Warnings
and Precautions (5.5)]. 7.5 Lorazepam Under steady-state conditions for duloxetine (60 mg Q 12 hours)
and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not
affected by co-administration. 7.6 Temazepam Under steady-state conditions for duloxetine (20 mg qhs) and
temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by
co-administration. 7.7 Drugs that Affect Gastric Acidity Cymbalta has an enteric coating that resists dissolution until
reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In
extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may
undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in
patients with conditions that may slow gastric emptying (e.g., some diabetics).
Drugs that raise the gastrointestinal pH may lead to an earlier release of
duloxetine. However, co-administration of Cymbalta with aluminum- and
magnesium-containing antacids (51 mEq) or Cymbalta with famotidine, had no
significant effect on the rate or extent of duloxetine absorption after
administration of a 40 mg oral dose. It is unknown whether the concomitant
administration of proton pump inhibitors affects duloxetine absorption [see Warnings and Precautions (5.12)]. 7.8 Drugs Metabolized by CYP1A2 In vitro drug interaction studies
demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an
increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine)
resulting from induction is not anticipated, although clinical studies of
induction have not been performed. Duloxetine is an inhibitor of the CYP1A2
isoform in in vitro studies, and in two clinical
studies the average (90% confidence interval) increase in theophylline AUC was
7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice
daily). 7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was
administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg
dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold
[see Warnings and Precautions (5.10)]. 7.10 Drugs Metabolized by CYP2C9 Duloxetine does not inhibit the in
vitro enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9
substrates is therefore not anticipated, although clinical studies have not been
performed. 7.11 Drugs Metabolized by CYP3A Results of in vitro studies
demonstrate that duloxetine does not inhibit or induce CYP3A activity.
Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g.,
oral contraceptives and other steroidal agents) resulting from induction or
inhibition is not anticipated, although clinical studies have not been
performed. 7.12 Drugs Metabolized by CYP2C19 Results of in vitro studies
demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic
concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore
not anticipated, although clinical studies have not been performed. 7.13 Monoamine Oxidase Inhibitors [see Dosage and Administration (2.5), Contraindications (4.1), and Warnings
and Precautions (5.4)]. 7.14 Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including
Cymbalta, and the potential for serotonin syndrome, caution is advised when
Cymbalta is co-administered with other drugs that may affect the serotonergic
neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a
reversible non-selective MAOI), lithium, tramadol, or St. John's Wort. The
concomitant use of Cymbalta with other SSRIs, SNRIs or tryptophan is not
recommended [see Warnings and Precautions (5.4)]. 7.15 Triptans There have been rare postmarketing reports of serotonin syndrome
with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a
triptan is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases [see Warnings and Precautions (5.4)]. 7.16 Alcohol When Cymbalta and ethanol were administered several hours apart
so that peak concentrations of each would coincide, Cymbalta did not increase
the impairment of mental and motor skills caused by alcohol.
In the Cymbalta clinical trials database, three Cymbalta-treated patients had
liver injury as manifested by ALT and total bilirubin elevations, with evidence
of obstruction. Substantial intercurrent ethanol use was present in each of
these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions (5.2 and 5.10)]. 7.17 CNS Drugs [see Warnings and Precautions (5.10)]. 7.18 Drugs Highly Bound to Plasma Protein Because duloxetine is highly bound to plasma protein,
administration of Cymbalta to a patient taking another drug that is highly
protein bound may cause increased free concentrations of the other drug,
potentially resulting in adverse reactions.
Potent inhibitors of CYP1A2 should be avoided (7.1).
Potent inhibitors of CYP2D6 may increase duloxetine concentrations (7.2).
Duloxetine is a moderate inhibitor of CYP2D6 (7.9).
8 Use In Specific Populations
8.1 Pregnancy Teratogenic Effects, Pregnancy Category
C — In animal reproduction studies, duloxetine has been shown to have
adverse effects on embryo/fetal and postnatal development.
When duloxetine was administered orally to pregnant rats and rabbits during
the period of organogenesis, there was no evidence of teratogenicity at doses up
to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day]
and 4 times the human dose of 120 mg/day on a mg/m2
basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a
mg/m2 basis in rabbit). However, fetal weights were
decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD
and ≈1 times the human dose of 120 mg/day on a mg/m2
basis in rat; 3 times the MRHD and 2 times the human dose of 120 mg/day on a
mg/m2 basis in rabbits).
When duloxetine was administered orally to pregnant rats throughout gestation
and lactation, the survival of pups to 1 day postpartum and pup body weights at
birth and during the lactation period were decreased at a dose of 30 mg/kg/day
(5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore,
behaviors consistent with increased reactivity, such as increased startle
response to noise and decreased habituation of locomotor activity, were observed
in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and
reproductive performance of the progeny were not affected adversely by maternal
duloxetine treatment.
There are no adequate and well-controlled studies in pregnant women;
therefore, duloxetine should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. Nonteratogenic Effects — Neonates
exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs),
late in the third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding. Such complications can
arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability,
feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia,
hyperreflexia, tremor, jitteriness, irritability, and constant crying. These
features are consistent with either a direct toxic effect of SSRIs and SNRIs or,
possibly, a drug discontinuation syndrome. It should be noted that, in some
cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.4)].
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
[see Dosage and Administration (2.3)]. 8.2 Labor and Delivery The effect of duloxetine on labor and delivery in humans is
unknown. Duloxetine should be used during labor and delivery only if the
potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Duloxetine is excreted into the milk of lactating women. The
estimated daily infant dose on a mg/kg basis is approximately 0.14% of the
maternal dose. Because the safety of duloxetine in infants is not known, nursing
while on Cymbalta is not recommended. However, if the physician determines that
the benefit of duloxetine therapy for the mother outweighs any potential risk to
the infant, no dosage adjustment is required as lactation did not influence
duloxetine pharmacokinetics.
The disposition of duloxetine was studied in 6 lactating women who were at
least 12 weeks postpartum. Duloxetine 40 mg twice daily was given for 3.5 days.
Like many other drugs, duloxetine is detected in breast milk, and steady state
concentrations in breast milk are about one-fourth those in plasma. The amount
of duloxetine in breast milk is approximately 7 μg/day while on 40 mg BID
dosing. The excretion of duloxetine metabolites into breast milk was not
examined. Because the safety of duloxetine in infants is not known, nursing
while on Cymbalta is not recommended [see Dosage and
Administration (2.3)]. 8.4 Pediatric Use Safety and effectiveness in the pediatric population have not
been established [see Boxed Warning and
Warnings and Precautions (5.1)]. Anyone considering
the use of Cymbalta in a child or adolescent must balance the potential risks
with the clinical need. 8.5 Geriatric Use Of the 2,418 patients in premarketing clinical studies of
Cymbalta for MDD, 5.9% (143) were 65 years of age or over. Of the 1,074 patients
in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the
1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or
over. Premarketing clinical studies of GAD did not include sufficient numbers of
subjects age 65 or over to determine whether they respond differently from
younger subjects. In the MDD, DPNP, and FM studies, no overall differences in
safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences
in responses between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out. SSRIs and SNRIs, including
Cymbalta have been associated with cases of clinically significant hyponatremia
in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.11)].
The pharmacokinetics of duloxetine after a single dose of 40 mg were compared
in healthy elderly females (65 to 77 years) and healthy middle-age females
(32 to 50 years). There was no difference in the Cmax,
but the AUC of duloxetine was somewhat (about 25%) higher and the half-life
about 4 hours longer in the elderly females. Population pharmacokinetic analyses
suggest that the typical values for clearance decrease by approximately 1% for
each year of age between 25 to 75 years of age; but age as a predictive factor
only accounts for a small percentage of between-patient variability. Dosage
adjustment based on the age of the patient is not necessary [see Dosage and Administration (2.3)]. 8.6 Gender Duloxetine's half-life is similar in men and women. Dosage
adjustment based on gender is not necessary. 8.7 Smoking Status Duloxetine bioavailability (AUC) appears to be reduced by about
one-third in smokers. Dosage modifications are not recommended for
smokers. 8.8 Race No specific pharmacokinetic study was conducted to investigate
the effects of race. 8.9 Hepatic Insufficiency Patients with clinically evident hepatic insufficiency have
decreased duloxetine metabolism and elimination. After a single 20 mg dose of
Cymbalta, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class
B) had a mean plasma duloxetine clearance about 15% that of age- and
gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC).
Although Cmax was similar to normals in the cirrhotic
patients, the half-life was about 3 times longer [see Dosage
and Administration (2.3) and Warnings and Precautions (5.12)].
8.10 Severe Renal Impairment Limited data are available on the effects of duloxetine in
patients with end-stage renal disease (ESRD). After a single 60 mg dose of
duloxetine, Cmax and AUC values were approximately 100%
greater in patients with end-stage renal disease receiving chronic intermittent
hemodialysis than in subjects with normal renal function. The elimination
half-life, however, was similar in both groups. The AUCs of the major
circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy,
6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7-
to 9-fold higher and would be expected to increase further with multiple dosing.
Population PK analyses suggest that mild to moderate degrees of renal
dysfunction (estimated CrCl 30-80 mL/min) have no significant effect on
duloxetine apparent clearance [see Dosage and Administration
(2.3) and Warnings and Precautions (5.12)].
Pregnancy and Nursing Mothers: Use only if the potential benefit justifies the
potential risk to the fetus or child (2.3, 8.1, 8.3).
9 Drug Abuse And Dependence
9.2 Abuse In animal studies, duloxetine did not demonstrate
barbiturate-like (depressant) abuse potential.
While Cymbalta has not been systematically studied in humans for its
potential for abuse, there was no indication of drug-seeking behavior in the
clinical trials. However, it is not possible to predict on the basis of
premarketing experience the extent to which a CNS active drug will be misused,
diverted, and/or abused once marketed. Consequently, physicians should carefully
evaluate patients for a history of drug abuse and follow such patients closely,
observing them for signs of misuse or abuse of Cymbalta (e.g., development of
tolerance, incrementation of dose, drug-seeking behavior). 9.3 Dependence In drug dependence studies, duloxetine did not demonstrate
dependence-producing potential in rats.
10 Overdosage
10.1 Signs and Symptoms In postmarketing experience, fatal outcomes have been reported
for acute overdoses, primarily with mixed overdoses, but also with duloxetine
only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine
alone or with mixed drugs) included somnolence, coma, serotonin syndrome,
seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. 10.2 Management of Overdose There is no specific antidote to Cymbalta, but if serotonin
syndrome ensues, specific treatment (such as with cyproheptadine and/or
temperature control) may be considered. In case of acute overdose, treatment
should consist of those general measures employed in the management of overdose
with any drug.
An adequate airway, oxygenation, and ventilation should be assured, and
cardiac rhythm and vital signs should be monitored. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate
airway protection, if needed, may be indicated if performed soon after ingestion
or in symptomatic patients.
Activated charcoal may be useful in limiting absorption of duloxetine from
the gastrointestinal tract. Administration of activated charcoal has been shown
to decrease AUC and Cmax by an average of one-third,
although some subjects had a limited effect of activated charcoal. Due to the
large volume of distribution of this drug, forced diuresis, dialysis,
hemoperfusion, and exchange transfusion are unlikely to be beneficial.
In managing overdose, the possibility of multiple drug involvement should be
considered. A specific caution involves patients who are taking or have recently
taken Cymbalta and might ingest excessive quantities of a TCA. In such a case,
decreased clearance of the parent tricyclic and/or its active metabolite may
increase the possibility of clinically significant sequelae and extend the time
needed for close medical observation [see Warnings and
Precautions (5.4) and Drug Interactions (7)]. The physician should consider contacting a poison
control center for additional information on the treatment of any overdose.
Telephone numbers for certified poison control centers are uled in the Physicians' Desk Reference (PDR).
11 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. The empirical formula is C18H19NOS•HCl, which corresponds to a molecular weight of 333.88.
The structural formula is: 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.
12 Clinical Pharmacology
12.1 Mechanism of Action Although the exact mechanisms of the antidepressant, central pain
inhibitory and anxiolytic actions of duloxetine in humans are unknown, these
actions are believed to be related to its potentiation of serotonergic and
noradrenergic activity in the CNS. 12.2 Pharmacodynamics 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).
Cymbalta is in a class of drugs known to affect urethral resistance. If
symptoms of urinary hesitation develop during treatment with Cymbalta,
consideration should be given to the possibility that they might be
drug-related. 12.3 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. Elimination of duloxetine is mainly through hepatic
metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Absorption and Distribution — Orally
administered duloxetine hydrochloride is well absorbed. There is a median 2 hour
lag until absorption begins (Tlag), with maximal plasma
concentrations (Cmax) of duloxetine occurring 6 hours
post dose. Food does not affect the Cmax of duloxetine,
but delays the time to reach peak concentration from 6 to 10 hours and it
marginally decreases the extent of absorption (AUC) by about 10%. There is a 3
hour delay in absorption and a one-third increase in apparent clearance of
duloxetine after an evening dose as compared to a morning dose.
The apparent volume of distribution averages about 1640 L. Duloxetine is
highly bound (>90%) to proteins in human plasma, binding primarily to albumin
and α1-acid glycoprotein. The interaction between
duloxetine and other highly protein bound drugs has not been fully evaluated.
Plasma protein binding of duloxetine is not affected by renal or hepatic
impairment. Metabolism and Elimination —
Biotransformation and disposition of duloxetine in humans have been determined
following oral administration of 14C-labeled duloxetine.
Duloxetine comprises about 3% of the total radiolabeled material in the plasma,
indicating that it undergoes extensive metabolism to numerous metabolites. The
major biotransformation pathways for duloxetine involve oxidation of the
naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and
CYP2D6 catalyze the oxidation of the naphthyl ring in
vitro. Metabolites found in plasma include 4-hydroxy duloxetine
glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional
metabolites have been identified in urine, some representing only minor pathways
of elimination. Only trace (less than 1% of the dose) amounts of unchanged duloxetine
are present in the urine. Most (about 70%) of the duloxetine dose appears in the
urine as metabolites of duloxetine; about 20% is excreted in the feces.
Duloxetine undergoes extensive metabolism, but the major circulating metabolites
have not been shown to contribute significantly to the pharmacologic activity of
duloxetine.
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, and Impairment of
Fertility Carcinogenesis — Duloxetine was
administered in the diet to mice and rats for 2 years.
In female mice receiving duloxetine at 140 mg/kg/day (11 times the maximum
recommended human dose [MRHD, 60 mg/day] and 6 times the human dose of 120
mg/day on a mg/m2 basis), there was an increased
incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50
mg/kg/day (4 times the MRHD and 2 times the human dose of 120 mg/day on a
mg/m2 basis). Tumor incidence was not increased in male
mice receiving duloxetine at doses up to 100 mg/kg/day (8 times the MRHD and 4
times the human dose of 120 mg/day on a mg/m2 basis).
In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (4 times
the MRHD and 2 times the human dose of 120 mg/day on a mg/m2 basis) and up to 36 mg/kg/day in males (6 times the MRHD and
3 times the human dose of 120 mg/day on a mg/m2 basis)
did not increase the incidence of tumors. Mutagenesis — Duloxetine was not
mutagenic in the in vitro bacterial reverse mutation
assay (Ames test) and was not clastogenic in an in
vivo chromosomal aberration test in mouse bone marrow cells.
Additionally, duloxetine was not genotoxic in an in
vitro mammalian forward gene mutation assay in mouse lymphoma cells or in
an in vitro unscheduled DNA synthesis (UDS) assay in
primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese
hamster bone marrow in vivo. Impairment of Fertility — Duloxetine
administered orally to either male or female rats prior to and throughout mating
at doses up to 45 mg/kg/day (7 times the maximum recommended human dose of 60
mg/day and 4 times the human dose of 120 mg/day on a mg/m2 basis) did not alter mating or fertility.
14 Clinical Studies
14.1 Major Depressive Disorder The efficacy of Cymbalta as a treatment for depression was
established in 4 randomized, double-blind, placebo-controlled, fixed-dose
studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major
depression. In 2 studies, patients were randomized to Cymbalta 60 mg once daily
(N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9
weeks; in the third study, patients were randomized to Cymbalta 20 or 40 mg
twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the
fourth study, patients were randomized to Cymbalta 40 or 60 mg twice daily (N=95
and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that
doses greater than 60 mg/day confer additional benefits.
In all 4 studies, Cymbalta demonstrated superiority over placebo as measured
by improvement in the 17-li Hamilton Depression Rating Scale (HAMD-17) total
score.
In all of these clinical studies, analyses of the relationship between
treatment outcome and age, gender, and race did not suggest any differential
responsiveness on the basis of these patient characteristics.
In another study, 533 patients meeting DSM-IV criteria for MDD received
Cymbalta 60 mg once daily during an initial 12-week open-label treatment phase.
Two hundred and seventy-eight patients who responded to open label treatment
(defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total
score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting
the DSM-IV criteria for MDD) were randomly assigned to continuation of Cymbalta
at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on
Cymbalta experienced a statistically significantly longer time to relapse of
depression than did patients on placebo. Relapse was defined as an increase in
the CGI–S score of ≥2 points compared with that obtained at week 12, as well as
meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks
apart, where the 2-week temporal criterion had to be satisfied at only the
second visit. The effectiveness of Cymbalta in hospitalized patients with major
depressive disorder has not been studied. 14.2 Generalized Anxiety Disorder The efficacy of Cymbalta in the treatment of generalized anxiety
disorder (GAD) was established in 1 fixed-dose randomized, double-blind,
placebo-controlled trial and 2 flexible-dose randomized, double-blind,
placebo-controlled trials in adult outpatients between 18 and 83 years of age
meeting the DSM-IV criteria for GAD.
In 1 flexible-dose study and in the fixed-dose study, the starting dose was
60 mg once daily where down titration to 30 mg once daily was allowed for
tolerability reasons before increasing it to 60 mg once daily. Fifteen percent
of patients were down titrated. One flexible-dose study had a starting dose of
30 mg once daily for 1 week before increasing it to 60 mg once daily.
The 2 flexible-dose studies involved dose titration with Cymbalta doses
ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to
placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for
completers at endpoint in the flexible-dose studies was 104.75 mg/day. The
fixed-dose study evaluated Cymbalta doses of 60 mg once daily (N=168) and 120 mg
once daily (N=170) compared to placebo (N=175) over a 9-week treatment period.
While a 120 mg/day dose was shown to be effective, there is no evidence that
doses greater than 60 mg/day confer additional benefit.
In all 3 studies, Cymbalta demonstrated superiority over placebo as measured
by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score and by
the Sheehan Disability Scale (SDS) global functional impairment score. The SDS
is a widely used and well-validated scale that measures the extent emotional
symptoms disrupt patient functioning in 3 life domains: work/school, social
life/leisure activities, and family life/home responsibilities.
In another study, 887 patients meeting DSM-IV-TR criteria for GAD received
Cymbalta 60 mg to 120 mg once daily during an initial 26-week open-label
treatment phase. Four hundred and twenty-nine patients who responded to
open-label treatment (defined as meeting the following criteria at weeks 24 and
26: a decrease from baseline HAM-A total score by at least 50% to a score no
higher than 11, and a Clinical Global Impressions of Improvement
[CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of
Cymbalta at the same dose (N = 216) or to placebo (N = 213) and were observed
for relapse. Of the patients randomized, 73% had been in a responder status for
at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at
least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric
Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack
of efficacy. Patients taking Cymbalta experienced a statistically significantly
longer time to relapse of GAD than did patients taking placebo.
Subgroup analyses did not indicate that there were any differences in
treatment outcomes as a function of age or gender. 14.3 Diabetic Peripheral Neuropathic Pain The efficacy of Cymbalta for the management of neuropathic pain
associated with diabetic peripheral neuropathy was established in 2 randomized,
12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients
having diabetic peripheral neuropathic pain for at least 6 months. Study 1 and 2
enrolled a total of 791 patients of whom 592 (75%) completed the studies.
Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful
distal symmetrical sensorimotor polyneuropathy for at least 6 months. The
patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no
pain) to 10 (worst possible pain). Patients were permitted up to 4 g of
acetaminophen per day as needed for pain, in addition to Cymbalta. Patients
recorded their pain daily in a diary.
Both studies compared Cymbalta 60 mg once daily or 60 mg twice daily with
placebo. Study 1 additionally compared Cymbalta 20 mg with placebo. A total of
457 patients (342 Cymbalta, 115 placebo) were enrolled in Study 1 and a total of
334 patients (226 Cymbalta, 108 placebo) were enrolled in Study 2. Treatment
with Cymbalta 60 mg one or two times a day statistically significantly improved
the endpoint mean pain scores from baseline and increased the proportion of
patients with at least a 50% reduction in pain score from baseline. For various
degrees of improvement in pain from baseline to study endpoint, Figures 1 and 2
show the fraction of patients achieving that degree of improvement. The figures
are cumulative, so that patients whose change from baseline is, for
example, 50%, are also included at every level of improvement below 50%.
Patients who did not complete the study were assigned 0% improvement. Some
patients experienced a decrease in pain as early as week 1, which persisted
throughout the study.
Figure 1: Percentage of Patients Achieving Various Levels of Pain Relief as
Measured by 24-Hour Average Pain Severity - Study 1
Figure 2: Percentage of Patients Achieving Various
Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - Study
2
14.4 Fibromyalgia The efficacy of Cymbalta for the management of fibromyalgia was
established in two randomized, double-blind, placebo-controlled, fixed-dose
studies in adult patients meeting the American College of Rheumatology criteria
for fibromyalgia (a history of widespread pain for 3 months, and pain present at
11 or more of the 18 specific tender point sites). Study 1 was three months in
duration and enrolled female patients only. Study 2 was six months in duration
and enrolled male and female patients. Approximately 25% of participants had a
comorbid diagnosis of major depressive disorder (MDD). Study 1 and 2 enrolled a
total of 874 patients of whom 541 (62%) completed the studies. The patients had
a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10
(worse possible pain).
Both studies compared Cymbalta 60 mg once daily or 120 mg daily (given in
divided doses in Study 1 and as a single daily dose in Study 2) with placebo.
Study 2 additionally compared Cymbalta 20 mg with placebo during the initial
three months of a six-month study. A total of 354 patients (234 Cymbalta, 120
placebo) were enrolled in Study 1 and a total of 520 patients (376 Cymbalta, 144
placebo) were enrolled in Study 2 (5% male, 95% female). Treatment with Cymbalta
60 mg or 120 mg daily statistically significantly improved the endpoint mean
pain scores from baseline and increase the proportion of patients with at least
a 50% reduction in pain score from baseline. Pain reduction was observed in
patients both with and without comorbid MDD. However, the degree of pain
reduction may be greater in patients with comorbid MDD. For various degrees of
improvement in pain from baseline to study endpoint, Figures 3 and 4 show the
fraction of patients achieving that degree of improvement. The figures are
cumulative so that patients whose change from baseline is, for example, 50%, are
also included at every level of improvement below 50%. Patients who did not
complete the study were assigned 0% improvement. Some patients experienced a
decrease in pain as early as week 1, which persisted throughout the study.
Improvement was also demonstrated on measures of function (Fibromyalgia Impact
Questionnaires) and patient global impression of change (PGI). Neither study
demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was
associated with more adverse reactions and premature discontinuations of
treatment.
Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as
Measured by 24-Hour Average Pain Severity - Study 1
Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as
Measured by 24-Hour Average Pain Severity - Study 2
Additionally, the benefit of up-titration in non-responders to Cymbalta at 60
mg/day was evaluated in a separate study. Patients were initially treated with
Cymbalta 60 mg once daily for eight weeks in open-label fashion. Subsequently,
completers of this phase were randomized to double-blind treatment with Cymbalta
at either 60 mg once daily or 120 mg once daily. Those patients who were
considered non-responders, where response was defined as at least a 30%
reduction in pain score from baseline at the end of the 8-week treatment, were
no more likely to meet response criteria at the end of 60 weeks of treatment if
blindly titrated to Cymbalta 120 mg as compared to those who were blindly
continued on Cymbalta 60 mg.
16 How Supplied/storage And Handling
16.1 How Supplied Cymbalta is available as delayed release capsules in the
following strengths, colors, imprints, and presentations:
Features
Strengths
20 mga
30 mga
60 mga
Body color
Opaque green
Opaque white
Opaque green
Cap Color
Opaque green
Opaque blue
Opaque blue
Cap imprint
Lilly 3235
Lilly 3240
Lilly 3237
Body imprint
20mg
30mg
60mg
Capsule number
PU3235
PU3240
PU3237
Presentations and NDC Codes
Bottles of 30
54868-5215-2
54868-5315-0
54868-5192-0
Bottles of 60
54868-5215-0
54868-5315-2
54868-5192-2
Bottles of 90
54868-5215-1
54868-5315-1
54868-5192-1
Bottles of 180
NA
NA
54868-5192-3
a equivalent to duloxetine base
16.2 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
[see USP Controlled Room Temperature].
Prescribers or other health professionals should inform patients,
their families, and their caregivers about the benefits and risks associated
with treatment with Cymbalta and should counsel them in its appropriate use. A
patient Medication Guide About Using Antidepressants in Children and Teenagers
is available for Cymbalta. 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 Cymbalta.
17.2 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 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
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 [see Boxed Warning, and
Warnings and Precautions (5.1)].
17.3 Medication Administration
Cymbalta should be swallowed whole and should not be chewed or crushed, nor
should the capsule be opened and its contents be sprinkled on food or mixed with
liquids. All of these might affect the enteric coating.
17.4 Continuing the Therapy Prescribed
While patients may notice improvement with Cymbalta therapy in 1 to 4 weeks,
they should be advised to continue therapy as directed.
17.5 Abnormal Bleeding
Patients should be cautioned about the concomitant use of duloxetine and NSAIDs,
aspirin, warfarin, or other drugs that affect coagulation since combined use of
psychotropic drugs that interfere with serotonin reuptake and these agents has
been associated with an increased risk of bleeding [see
Warnings and Precautions (5.5)].
17.6 Concomitant Medications
Patients should be advised to inform their physicians if they are taking, or
plan to take, any prescription or over-the-counter medications, since there is a
potential for interactions [see Dosage and Administration
(2.5), Contraindications (4.1), Warnings
and Precautions (5.4 and 5.10), and Drug
Interactions (7)].
17.7 Serotonin Syndrome
Patients should be cautioned about the risk of serotonin syndrome with the
concomitant use of Cymbalta and triptans, tramadol or other serotonergic agents
[see Warnings and Precautions (5.4) and
Drug Interactions (7.14)].
17.8 Pregnancy and Breast Feeding
Patients should be advised to notify their physician if they
become pregnant during therapy
intend to become pregnant during therapy
are breast feeding [see Dosage and Administration (2.3) and Use in Specific Populations (8.1, 8.2, and 8.3)].
17.9 Alcohol
Although Cymbalta does not increase the impairment of mental and motor skills
caused by alcohol, use of Cymbalta concomitantly with heavy alcohol intake may
be associated with severe liver injury. For this reason, Cymbalta should
ordinarily not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug
Interactions (7.16)].
17.10 Orthostatic Hypotension and Syncope
Patients should be advised of the risk of orthostatic hypotension and syncope,
especially during the period of initial use and subsequent dose escalation, and
in association with the use of concomitant drugs that might potentiate the
orthostatic effect of duloxetine [see Warnings and
Precautions (5.3)].
17.11 Interference with Psychomotor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills. Although
in controlled studies Cymbalta has not been shown to impair psychomotor
performance, cognitive function, or memory, it may be associated with sedation
and dizziness. Therefore, patients should be cautioned about operating hazardous
machinery including automobiles, until they are reasonably certain that Cymbalta
therapy does not affect their ability to engage in such activities.
Antidepressant Medicines, Depression and other Serious
Mental Illnesses, and Suicidal Thoughts or Actions
Read the Medication Guide that comes with your or your family member's
antidepressant medicine. This Medication Guide is only about the risk of
suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider
about:
all risks and benefits of treatment with antidepressant medicines
all treatment choices for depression or other serious mental
illness
What is the most important information I should know about
antidepressant medicines, depression and other serious mental illnesses, and
suicidal thoughts or actions?
Antidepressant medicines may increase suicidal thoughts or
actions in some children, teenagers, and young adults within the first few
months of treatment.
Depression and other serious mental illnesses are the most
important causes of suicidal thoughts and actions. Some people may have a
particularly high risk of having suicidal thoughts or actions. These
include people who have (or have a family history of) bipolar illness (also
called manic-depressive illness) or suicidal thoughts or actions.
How can I watch for and try to prevent suicidal thoughts
and actions in myself or a family member?
Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
Keep all follow-up visits with the healthcare provider as scheduled. Call
the healthcare provider between visits as needed, especially if you have
concerns about symptoms.
Call a healthcare provider right away if you or your family
member has any of the following symptoms, especially if they are new, worse, or
worry you:
thoughts about suicide or dying
attempts to commit suicide
new or worse depression
new or worse anxiety
feeling very agitated or restless
panic attacks
trouble sleeping (insomnia)
new or worse irritability
acting aggressive, being angry, or violent
acting on dangerous impulses
an extreme increase in activity and talking (mania)
other unusual changes in behavior or mood
What else do I need to know about antidepressant
medicines?
Never stop an antidepressant medicine without first talking
to a healthcare provider. Stopping an antidepressant medicine suddenly
can cause other symptoms.
Antidepressants are medicines used to treat depression and
other illnesses. It is important to discuss all the risks of treating
depression and also the risks of not treating it. Patients and their families or
other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.
Antidepressant medicines have other side effects.
Talk to the healthcare provider about the side effects of the medicine
prescribed for you or your family member.
Antidepressant medicines can interact with other
medicines. Know all of the medicines that you or your family member
takes. Keep a ul of all medicines to show the healthcare provider. Do not
start new medicines without first checking with your healthcare provider.
Not all antidepressant medicines prescribed for children
are FDA approved for use in children. Talk to your child's healthcare
provider for more information.
These are not all the possible side effects. Call your doctor for medical
advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the US Food
and Drug Administration for all antidepressants.
Patient Information revised December 4, 2008
PV 7090 AMP
Principal Display Panel
Cymbalta®
Duloxetine HCl DELAYED RELEASE CAPSULES
20 mg
Each capsule contains 22.4 mg of duloxetine hydrochloride equivalent to 20 mg
duloxetine.
Rx Only
www.Cymbalta.com
Cymbalta®
duloxetine HCl DELAYED RELEASE CAPSULES
30 mg
Each capsule contains 33.7 mg of duloxetine hydrochloride equivalent to 30 mg
duloxetine.
Rx Only
www.Cymbalta.com
Cymbalta®
duloxetine HCl DELAYED RELEASE CAPSULES
60 mg
Each capsule contains 67.3 mg of duloxetine hydrochloride equivalent to 60 mg
duloxetine.
Rx Only
www.Cymbalta.com
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