Ive tried the euro product and it doesnt live up to the hype.
The most similar ive found in the U.S. is cymbalta which was much stronger with immediate results.
<p>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:</p>
<p align="center">
<img src="images/cymbalta1%5B1%5D.gif" width="226" border="0" height="144"></p>
<p>Duloxetine hydrochloride is a white to slightly brownish white solid,
which is slightly soluble in water.</p>
<p>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.</p>
<p><b><font size="+1" color="#5a7b9e">Clinical <a name="pharmacology">Pharmacology</a></font></b></p>
<p><b>Pharmacodynamics</b> <br>
Although the exact mechanisms of the antidepressant and central pain inhibitory
action of duloxetine in humans are unknown, the antidepressant and pain
inhibitory actions are believed to be related to its potentiation of
serotonergic and noradrenergic activity in the CNS. Preclinical studies have
shown that duloxetine is a potent inhibitor of neuronal serotonin and
norepinephrine reuptake and a less potent inhibitor of dopamine reuptake.
Duloxetine has no significant affinity for dopaminergic, adrenergic,
cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro.
Duloxetine does not inhibit monoamine oxidase (MAO). Duloxetine undergoes
extensive metabolism, but the major circulating metabolites have not been shown
to contribute significantly to the pharmacologic activity of duloxetine.</p>
<p><b>Pharmacokinetics</b> <br>
Duloxetine has an elimination half-life of about 12 hours (range 8 to 17
hours) and its pharmacokinetics are dose proportional over the therapeutic
range. Steady-state plasma concentrations are typically achieved after 3
days of dosing. Elimination of duloxetine is mainly through hepatic
metabolism involving two P450 isozymes, CYP2D6 and CYP1A2.</p>
<p><i>Absorption and Distribution</i> — 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.</p>
<p>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.</p>
<p>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 CYP2D6 and CYP1A2 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 (<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.</p>
<p><b>Special Populations</b></p>
<p>Gender — Duloxetine’s half-life is similar in men and women. Dosage
adjustment based on gender is not necessary.</p>
<p>Age — 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 <a href="#dosage">DOSAGE AND ADMINISTRATION</a>).</p>
<p>Smoking Status — Duloxetine bioavailability (AUC) appears to be reduced
by about one-third in smokers. Dosage modifications are not recommended for
smokers.</p>
<p>Race — No specific pharmacokinetic study was conducted to investigate the
effects of race.</p>
<p>Renal Insufficiency — 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. For this reason, Cymbalta is not recommended for
patients with end-stage renal disease (requiring dialysis) or severe renal
impairment (estimated creatinine clearance [CrCl] <30 mL/min) (see
<a href="#dosage">DOSAGE AND ADMINISTRATION</a>). 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.</p>
<p>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
<a href="#precautions">PRECAUTIONS</a>). It is recommended that duloxetine
not be administered to patients with any hepatic insufficiency (see
<a href="#dosage">DOSAGE AND ADMINISTRATION</a>).</p>
<p><b>Drug-Drug Interactions (also see <a href="#precautions">PRECAUTIONS</a>,
<a href="#drug">Drug Interactions</a>)</b></p>
<p>Potential for Other Drugs to Affect Duloxetine<br>
Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.</p>
<p>Inhibitors of CYP1A2 — When duloxetine was co-administered with
fluvoxamine, a potent CYP1A2 inhibitor, to male subjects (n=14) the 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.</p>
<p>Inhibitors of CYP2D6 — 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 of
duloxetine (see <a href="#precautions">PRECAUTIONS</a>, Drug Interactions).</p>
<p><i>Studies with Benzodiazepines</i><br>
<i>Lorazepam</i> — 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.</p>
<p><i>Temazepam</i> — Under steady-state conditions for duloxetine (20 mg
qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not
affected by co-administration.</p>
<p>Potential for Duloxetine to Affect Other Drugs</p>
<p>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. Although duloxetine is an
inhibitor of the CYP1A2 isoform in in vitro studies, the pharmacokinetics of
theophylline, a CYP1A2 substrate, were not significantly affected by
co-administration with duloxetine (60 mg BID). Duloxetine is thus unlikely
to have a clinically significant effect on the metabolism of CYP1A2
substrates.</p>
<p>Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of
CYP2D6 and increases the AUC and Cmax of drugs metabolized by CYP2D6 (see
PRECAUTIONS). Therefore, co-administration of Cymbalta with other drugs that
are extensively metabolized by this isozyme and that have a narrow
therapeutic index should be approached with caution (see PRECAUTIONS, Drug
Interactions).</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p><i>Studies with Benzodiazepines<br>
Lorazepam</i> — Under steady-state conditions for duloxetine (60 mg Q 12
hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of lorazepam
were not affected by co-administration.</p>
<p><i>Temazepam</i> — Under steady-state conditions for duloxetine (20 mg
qhs) and temazepam (30 mg qhs), the pharmacokinetics of temazepam were not
affected by co-administration.</p>
<p>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 events.</p>
<p><b><font size="+1" color="#5a7b9e"><a name="Clinical_Studies">Clinical
Studies</a></font></b></p>
<p><b>Major Depressive Disorder</b></p>
<p>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 any additional benefit.</p>
<p>In all 4 studies, Cymbalta demonstrated superiority over placebo as
measured by improvement in the 17-item Hamilton Depression Rating Scale
(HAMD-17) total score.</p>
<p>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.</p>
<p><b>Diabetic Peripheral Neuropathic Pain<br>
</b>The efficacy of Cymbalta for the management of neuropathic pain
associated with diabetic peripheral neuropathy (DPN) was established in 2
randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in
adult patients having diabetic peripheral neuropathy 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.</p>
<p>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.</p>
<p><img src="images/cymbalta2%5B1%5D.gif" width="424" border="0" height="205"></p>
<p align="center">Percent Improvement in Pain from Baseline<br>
<b>Figure 1: Percentage of Patients Achieving Various Levels of Pain Relief
as Measured by 24-Hour Average Pain Severity - Study 1</b></p>
<p><img src="images/cymbalta3%5B1%5D.gif" width="419" border="0" height="198"></p>
<p align="center">Percent Improvement in Pain from Baseline<br>
<b>Figure 2: Percentage of Patients Achieving Various Levels of Pain Relief
as Measured by 24-Hour Average Pain Severity - Study 2</b></p>
<p><font size="2" face="Arial"><a href="#top">top</a></font></p>
<p><b><a name="indications"><font size="+1" color="#5a7b9e">Indications</font></a><font size="+1" color="#5a7b9e">
and Usage</font></b></p>
<p><b>Major Depressive Disorder </b> </p>
<p>Cymbalta is indicated for the treatment of major depressive disorder
(MDD).</p>
<p>The efficacy of Cymbalta has been established in 8- and 9-week
placebo-controlled trials of outpatients who met DSM-IV diagnostic criteria
for major depressive disorder (see CLINICAL STUDIES).</p>
<p>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.</p>
<p>The effectiveness of Cymbalta in hospitalized patients with major
depressive disorder has not been studied.</p>
<p>The effectiveness of Cymbalta in long-term use for major depressive
disorder, that is, for more than 9 weeks, has not been systematically
evaluated in controlled trials. The physician who elects to use Cymbalta for
extended periods should periodically evaluate the long-term usefulness of
the drug for the individual patient.</p>
<p><b>Diabetic Peripheral Neuropathic Pain</b></p>
<p>Cymbalta is indicated for the management of neuropathic pain associated
with diabetic peripheral neuropathy (see <a href="#Clinical_Studies">
CLINICAL STUDIES</a>).</p>
<p><font size="2" face="Arial"><a href="#top">top</a></font></p>
<p><b><a name="contraindications"><font size="+1" color="#5a7b9e">Contraindications</font></a></b></p>
<p><b>Hypersensitivity</b> <br>
Cymbalta is contraindicated in patients with a known hypersensitivity to
duloxetine or any of the inactive ingredients.</p>
<p><b>Monoamine Oxidase Inhibitors <br>
</b>Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs)
is contraindicated (see WARNINGS).</p>
<p><b>Uncontrolled Narrow-Angle Glaucoma <br>
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.</b></p>
<p><font size="2" face="Arial"><a href="#top">top</a></font></p>
<p><b><a name="warnings"><font size="+1" color="#5a7b9e">Warnings</font></a>
</b> </p>
<p><b>Clinical Worsening and
Suicide Risk</b> — Patients with major depressive disorder (MDD), both adult and
pediatric, may experience worsening of their depression and/or the emergence of
suicidal ideation and behavior (suicidality) or unusual changes in behavior,
whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. There has been a long-standing
concern that antidepressants may have a role in inducing worsening of depression
and the emergence of suicidality in certain patients. Antidepressants increased
the risk of suicidal thinking and behavior (suicidality) in short-term studies
in children and adolescents with major depressive disorder (MDD) and other
psychiatric disorders.</p>
<p>Pooled analyses of short-term placebo-controlled trials of 9
antidepressant drugs (SSRIs and others) in children and adolescents with
MDD, OCD, or other psychiatric disorders (a total of 24 trials involving
over 4400 patients) have revealed a greater risk of adverse events
representing suicidal behavior or thinking (suicidality) during the first
few months of treatment in those receiving antidepressants. The average risk
of such events in patients receiving antidepressants was 4%, twice the
placebo risk of 2%. There was considerable variation in risk among drugs,
but a tendency toward an increase for almost all drugs studied. The risk of
suicidality was most consistently observed in the MDD trials, but there were
signals of risk arising from some trials in other psychiatric indications
(obsessive compulsive disorder and social anxiety disorder) as well. No
suicides occurred in any of these trials. It is unknown whether the
suicidality risk in pediatric patients extends to longer-term use, i.e.,
beyond several months. It is also unknown whether the suicidality risk
extends to adults.</p>
<p><b>All pediatric patients being treated with antidepressants for any
indication should be observed closely for clinical worsening, suicidality,
and unusual changes in behavior, especially during the initial few months of
a course of drug therapy, or at times of dose changes, either increases or
decreases. Such observation would generally include at least weekly
face-to-face contact with patients or their family members or caregivers
during the first 4 weeks of treatment, then every other week visits for the
next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks.
Additional contact by telephone may be appropriate between face-to-face
visits.</b></p>
<p><b>Adults with MDD or co-morbid depression in the setting of other
psychiatric illness being treated with antidepressants should be observed
similarly for clinical worsening and suicidality, especially during the
initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases.</b></p>
<p>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.</p>
<p>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.</p>
<p>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.</p>
<p>If the decision has been made to discontinue treatment, medication should
be tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can be associated with certain symptoms (see
<a href="#precautions">PRECAUTIONS</a> and <a href="#overdose">DOSAGE AND
ADMINISTRATION</a>, Discontinuing Cymbalta, for a description of the risks
of discontinuation of Cymbalta).</p>
<p><b>Families and caregivers of pediatric patients being treated with
antidepressants for major depressive disorder or other indications, both
psychiatric and nonpsychiatric, should be alerted about the need to monitor
patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence
of suicidality, and to report such symptoms immediately to health care
providers. Such monitoring should include daily observation by families and
caregivers.</b></p>
<p>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. Families and caregivers of adults being treated for
depression should be similarly advised.</p>
<p><b>Screening Patients for Bipolar Disorder</b> — 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 is not approved for use in treating bipolar depression.</p>
<p><b>Monoamine Oxidase Inhibitors (MAOI) — In patients receiving a
serotonin reuptake inhibitor in combination with a monoamine oxidase
inhibitor, there have been reports of serious, sometimes fatal, reactions
including hyperthermia, rigidity, myoclonus, autonomic instability with
possible rapid fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma. These reactions
have also been reported in patients who have recently discontinued serotonin
reuptake inhibitors and are then started on an MAOI. Some cases presented
with features resembling neuroleptic malignant syndrome. The effects of
combined use of Cymbalta and MAOIs have not been evaluated in humans or
animals. Therefore, because Cymbalta is an inhibitor of both serotonin and
norepinephrine reuptake, it is recommended that Cymbalta not be used in
combination with an MAOI, or within at least 14 days of discontinuing
treatment with an MAOI. Based on the half-life of Cymbalta, at least 5 days
should be allowed after stopping Cymbalta before starting an MAOI.</b></p>
<p><font size="2" face="Arial"><a href="#top">top</a></font></p>
<p><b><a name="precautions"><font size="+1" color="#5a7b9e">Precautions</font></a></b></p>
<p><b>General</b> </p>
<p><b>Hepatotoxicity</b> — Cymbalta increases the risk of elevation of serum
transaminase levels. Liver transaminase elevations resulted in the
discontinuation of 0.4% (31/8454) of Cymbalta-treated patients. In these
patients, the median time to detection of the transaminase elevation was
about two months. In controlled trials in MDD, elevations of alanine
transaminase (ALT) to >3 times the upper limit of normal occurred in 0.9%
(8/930) of Cymbalta-treated patients and in 0.3% (2/652) of placebo-treated
patients. In controlled trials in DPN, elevations of ALT to >3 times the
upper limit of normal occurred in 1.68% (8/477) of Cymbalta-treated patients
and in 0% (0/187) of placebo-treated patients. In the full cohort of
placebo-controlled trials in any indication, 1% (39/3732) of
Cymbalta-treated patients had a >3 times the upper limit of normal elevation
of ALT compared to 0.2% (6/2568) 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 >3 times the upper
limit of normal and >5 times the upper limit of normal, respectively.
Postmarketing reports have described cases of 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. Cases of cholestatic jaundice with
minimal elevation of transaminase levels have also been reported.</p>
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The combination of transaminase elevations and elevated bilirubin,
without evidence of obstruction, is generally recognized as an important
predictor of severe liver injury. In clinical trials, three Cymbalta
patients had elevations of transaminases and bilirubin, but also had
elevation of alkaline phosphatase, suggesting an obstructive process; in
these patients, there was evidence of heavy alcohol use and this may have
contributed to the abnormalities seen. Two placebo-treated patients also had
transaminase elevations with elevated bilirubin. Postmarketing reports
indicate that elevated transaminases, bilirubin and alkaline phosphatase
have occurred in patients with chronic liver disease or cirrhosis. 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.</p>
<p><i>Effect on Blood Pressure</i> — In MDD clinical trials, Cymbalta
treatment was associated with mean increases in blood pressure, averaging 2
mm Hg systolic and 0.5 mm Hg diastolic and an increase in the incidence of
at least one measurement of systolic blood pressure over 140 mm Hg compared
to placebo.</p>
<p>Blood pressure should be measured prior to initiating treatment and
periodically measured throughout treatment (see <a href="#adverse">ADVERSE
REACTIONS</a>, Vital Sign Changes).</p>
<p><i>Activation of Mania/Hypomania</i> — In placebo-controlled trials in
patients with major depressive disorder, activation of mania or hypomania
was reported in 0.1% (1/1139) of Cymbalta-treated patients and 0.1% (1/777)
of placebo-treated patients. Activation of mania/hypomania has been reported
in a small proportion of patients with mood disorders who were treated with
other marketed drugs effective in the treatment of major depressive
disorder. As with these other agents, Cymbalta should be used cautiously in
patients with a history of mania.</p>
<p><i>Seizures</i> — Cymbalta has not been systematically evaluated in
patients with a seizure disorder, and such patients were excluded from
clinical studies. In placebo-controlled clinical trials in patients with
major depressive disorder, seizures occurred in 0.1% (1/1139) of patients
treated with Cymbalta and 0% (0/777) of patients treated with placebo. In
placebo-controlled clinical trials in patients with diabetic peripheral
neuropathy, seizures did not occur in any patients treated with either
Cymbalta or placebo. Cymbalta should be prescribed with care in patients
with a history of a seizure disorder.</p>
<p><i>Controlled Narrow-Angle Glaucoma</i> — 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
<a href="#contraindications">CONTRAINDICATIONS</a>, Uncontrolled
Narrow-Angle Glaucoma).</p>
<p><i>Discontinuation of Treatment with Cymbalta</i> — Discontinuation
symptoms have been systematically evaluated in patients taking Cymbalta.
Following abrupt discontinuation in MDD placebo-controlled clinical trials
of up to 9-weeks duration, the following symptoms occurred at a rate greater
than or equal to 2% and at a significantly higher rate in Cymbalta-treated
patients compared to those discontinuing from placebo: dizziness; nausea;
headache; paresthesia; vomiting; irritability; and nightmare.</p>
<p>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.</p>
<p>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
<a href="#dosage">DOSAGE AND ADMINISTRATION</a>).</p>
<p><i>Use in Patients with Concomitant Illness</i> — 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. As duloxetine is
rapidly hydrolyzed in acidic media to naphthol, caution is advised in using
Cymbalta in patients with conditions that may slow gastric emptying (e.g.,
some diabetics).</p>
<p>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. However, the electrocardiograms
of 321 patients who received Cymbalta in MDD placebo-controlled clinical
trials and had qualitatively normal ECGs at baseline were evaluated;
Cymbalta was not associated with the development of clinically significant
ECG abnormalities (see <a href="#adverse">ADVERSE REACTIONS</a>,
Electrocardiogram Changes).</p>
<p>In DPN placebo-controlled clinical trials, Cymbalta-treated patients did
not develop abnormal ECGs at a rate different from that in placebo-treated
patients (see <a href="#adverse">ADVERSE REACTIONS</a>, Electrocardiogram
Changes).</p>
<p>In clinical trials of Cymbalta for the management of neuropathic pain
associated with diabetic peripheral neuropathy, the mean duration of
diabetes was approximately 11 years, the mean baseline fasting blood glucose
was 163 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In
these studies, small increases in fasting blood glucose were observed in
Cymbalta-treated patients compared to placebo at 12 weeks and routine care
at 52 weeks. The increase was similar at both time points. Overall diabetic
control did not worsen as evidenced by stable HbA1c values and by no
differences in incidence of serious and non-serious diabetes-related adverse
events relative to placebo or routine care.</p>
<p>Increased plasma concentrations of duloxetine, and especially of its
metabolites, occur in patients with end-stage renal disease (requiring
dialysis). For this reason, Cymbalta is not recommended for patients with
end-stage renal disease or severe renal impairment (creatinine clearance <30
mL/min) (see <a href="#pharmacology">CLINICAL PHARMACOLOGY</a> and
<a href="#dosage">DOSAGE AND ADMINISTRATION</a>).</p>
<p>Markedly increased exposure to duloxetine occurs in patients with hepatic
insufficiency and Cymbalta should not be administered to these patients (see
<a href="#pharmacology">CLINICAL PHARMACOLOGY</a> and <a href="#dosage">
DOSAGE AND ADMINISTRATION</a>).</p>
<h4>Information for Patients</h4>
<p>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.</p>
<p>Patients should be advised of the following issues and asked to alert
their prescriber if these occur while taking Cymbalta.</p>
<p><i>Clinical Worsening and Suicide Risk</i> — 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.</p>
<p>Cymbalta should be swallowed whole and should not be chewed or crushed,
nor should the contents be sprinkled on food or mixed with liquids. All of
these might affect the enteric coating.</p>
<p>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.</p>
<p>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.</p>
<p>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.</p>