Cymbalta Information
Cymbalta (Duloxetine hydrochloride)
Cymbalta (Duloxetine hydrochloride) Indications And Usage
Cymbalta (Duloxetine hydrochloride) is indicated for the treatment of major depressive
disorder (MDD). The efficacy of Cymbalta (Duloxetine hydrochloride) was established in four short term and
one maintenance trial in adults .
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.
Cymbalta (Duloxetine hydrochloride) is indicated for the management of neuropathic pain
(DPNP) associated with diabetic peripheral neuropathy .
Cymbalta (Duloxetine hydrochloride) is indicated for the management of fibromyalgia (FM)
.
Cymbalta (Duloxetine hydrochloride) Dosage And Administration
Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride)
should be given without regard to meals.
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 .
Symptoms associated with discontinuation of Cymbalta (Duloxetine hydrochloride) and other
SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than
abrupt cessation is recommended whenever possible .
At least 14 days should elapse between discontinuation of an MAOI
and initiation of therapy with Cymbalta (Duloxetine hydrochloride) . In addition, at least 5 days should be
allowed after stopping Cymbalta (Duloxetine hydrochloride) before starting an MAOI .
Cymbalta (Duloxetine hydrochloride) Dosage Forms And Strengths
Cymbalta (Duloxetine hydrochloride) is available as delayed release capsules:
Cymbalta (Duloxetine hydrochloride) Contraindications
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 .
In clinical trials, Cymbalta (Duloxetine hydrochloride) use was associated with an increased
risk of mydriasis; therefore, its use should be avoided in patients with
uncontrolled narrow-angle glaucoma .
Cymbalta (Duloxetine hydrochloride) Warnings And Precautions
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 .
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.
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 for descriptions of the risks of discontinuation of
Cymbalta (Duloxetine hydrochloride) .
There have been reports of hepatic failure, sometimes fatal, in
patients treated with Cymbalta (Duloxetine hydrochloride) . 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) -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 (Duloxetine hydrochloride) -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 (Duloxetine hydrochloride) should ordinarily not be prescribed to patients with substantial
alcohol use or evidence of chronic liver disease.
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 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.
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.
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 (Duloxetine hydrochloride) . 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 .
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 (Duloxetine hydrochloride) should be used cautiously in patients with a
history of mania.
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 (Duloxetine hydrochloride) should be prescribed with care in
patients with a history of a seizure disorder.
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 .
Both CYP1A2 and CYP2D6 are responsible for duloxetine
metabolism.
Hyponatremia may occur as a result of treatment with SSRIs and
SNRIs, including Cymbalta (Duloxetine hydrochloride) . 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 (Duloxetine hydrochloride) 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 .
Discontinuation of Cymbalta (Duloxetine hydrochloride) 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.
Clinical experience with Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 's enteric
coating. In extremely acidic conditions, Cymbalta (Duloxetine hydrochloride) , unprotected by the enteric
coating, may undergo hydrolysis to form naphthol. Caution is advised in using
Cymbalta (Duloxetine hydrochloride) in patients with conditions that may slow gastric emptying (e.g., some
diabetics).
Cymbalta (Duloxetine hydrochloride) 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.
Cymbalta (Duloxetine hydrochloride) is in a class of drugs known to affect urethral
resistance. If symptoms of urinary hesitation develop during treatment with
Cymbalta (Duloxetine hydrochloride) , 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.
No specific laboratory tests are recommended.
Cymbalta (Duloxetine hydrochloride) Adverse Reactions
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 .
The stated frequencies of adverse reactions represent the proportion of
individuals who experienced, at least once, a treatment-emergent adverse
reaction of the type listed. 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.
In addition to the adverse reactions listed above, DPNP trials also included
dizziness and asthenia.
Cymbalta (Duloxetine hydrochloride)
Cymbalta (Duloxetine hydrochloride)
Cymbalta (Duloxetine hydrochloride) Drug Interactions
Both CYP1A2 and CYP2D6 are responsible for duloxetine
metabolism.
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 C was increased
about 2.5-fold, and duloxetine t was increased
approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include
cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin .
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) .
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 C.
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 .
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.
Under steady-state conditions for duloxetine (20 mg qhs) and
temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by
co-administration.
Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) , unprotected by the enteric coating, may
undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) with aluminum- and
magnesium-containing antacids (51 mEq) or Cymbalta (Duloxetine hydrochloride) 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 .
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
.
Duloxetine does not inhibit the enzyme activity of CYP2C9. Inhibition of the metabolism of CYP2C9
substrates is therefore not anticipated, although clinical studies have not been
performed.
Results of 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.
Results of 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.
Based on the mechanism of action of SNRIs and SSRIs, including
Cymbalta (Duloxetine hydrochloride) , and the potential for serotonin syndrome, caution is advised when
Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) with other SSRIs, SNRIs or tryptophan is not
recommended .
There have been rare postmarketing reports of serotonin syndrome
with use of an SSRI and a triptan. If concomitant treatment of Cymbalta (Duloxetine hydrochloride) with a
triptan is clinically warranted, careful observation of the patient is advised,
particularly during treatment initiation and dose increases .
When Cymbalta (Duloxetine hydrochloride) and ethanol were administered several hours apart
so that peak concentrations of each would coincide, Cymbalta (Duloxetine hydrochloride) did not increase
the impairment of mental and motor skills caused by alcohol.
In the Cymbalta (Duloxetine hydrochloride) clinical trials database, three Cymbalta (Duloxetine hydrochloride) -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 .
Because duloxetine is highly bound to plasma protein,
administration of Cymbalta (Duloxetine hydrochloride) 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.
Cymbalta (Duloxetine hydrochloride) Use In Specific Populations
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/m
basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a
mg/m 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/m
basis in rat; 3 times the MRHD and 2 times the human dose of 120 mg/day on a
mg/m 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/m 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.
When treating pregnant women with Cymbalta (Duloxetine hydrochloride) during the third trimester, the
physician should carefully consider the potential risks and benefits of
treatment. The physician may consider tapering Cymbalta (Duloxetine hydrochloride) in the third trimester
.
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.
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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) is not recommended .
Safety and effectiveness in the pediatric population have not
been established . Anyone considering
the use of Cymbalta (Duloxetine hydrochloride) in a child or adolescent must balance the potential risks
with the clinical need.
Of the 2,418 patients in premarketing clinical studies of
Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) have been associated with cases of clinically significant hyponatremia
in elderly patients, who may be at greater risk for this adverse event .
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 C,
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 .
Duloxetine's half-life is similar in men and women. Dosage
adjustment based on gender is not necessary.
Duloxetine bioavailability (AUC) appears to be reduced by about
one-third in smokers. Dosage modifications are not recommended for
smokers.
No specific pharmacokinetic study was conducted to investigate
the effects of race.
Patients with clinically evident hepatic insufficiency have
decreased duloxetine metabolism and elimination. After a single 20 mg dose of
Cymbalta (Duloxetine hydrochloride) , 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 C was similar to normals in the cirrhotic
patients, the half-life was about 3 times longer
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, C 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 .
Cymbalta (Duloxetine hydrochloride) Drug Abuse And Dependence
In animal studies, duloxetine did not demonstrate
barbiturate-like (depressant) abuse potential.
While Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) (e.g., development of
tolerance, incrementation of dose, drug-seeking behavior).
In drug dependence studies, duloxetine did not demonstrate
dependence-producing potential in rats.
Cymbalta (Duloxetine hydrochloride) Overdosage
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.
There is no specific antidote to Cymbalta (Duloxetine hydrochloride) , 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 C 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 (Duloxetine hydrochloride) 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 . 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 listed in the (PDR).
Cymbalta (Duloxetine hydrochloride) Description
Cymbalta (Duloxetine hydrochloride) is a selective
serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration.
Its chemical designation is (+)-()--methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine
hydrochloride. The empirical formula is CHNOS•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.
Cymbalta (Duloxetine hydrochloride) Clinical Pharmacology
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.
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 . Duloxetine does not inhibit
monoamine oxidase (MAO).
Cymbalta (Duloxetine hydrochloride) is in a class of drugs known to affect urethral resistance. If
symptoms of urinary hesitation develop during treatment with Cymbalta (Duloxetine hydrochloride) ,
consideration should be given to the possibility that they might be
drug-related.
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.
The apparent volume of distribution averages about 1640 L. Duloxetine is
highly bound (>90%) to proteins in human plasma, binding primarily to albumin
and α-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.
Cymbalta (Duloxetine hydrochloride) Nonclinical Toxicology
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/m 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/m 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/m 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/m 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/m basis)
did not increase the incidence of tumors.
Cymbalta (Duloxetine hydrochloride) Clinical Studies
The efficacy of Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) demonstrated superiority over placebo as measured
by improvement in the 17-item 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride)
at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on
Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) in hospitalized patients with major
depressive disorder has not been studied.
The efficacy of Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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.
The efficacy of Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) . Patients
recorded their pain daily in a diary.
Both studies compared Cymbalta (Duloxetine hydrochloride) 60 mg once daily or 60 mg twice daily with
placebo. Study 1 additionally compared Cymbalta (Duloxetine hydrochloride) 20 mg with placebo. A total of
457 patients (342 Cymbalta (Duloxetine hydrochloride) , 115 placebo) were enrolled in Study 1 and a total of
334 patients (226 Cymbalta (Duloxetine hydrochloride) , 108 placebo) were enrolled in Study 2. Treatment
with Cymbalta (Duloxetine hydrochloride) 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.
The efficacy of Cymbalta (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 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 (Duloxetine hydrochloride) 20 mg with placebo during the initial
three months of a six-month study. A total of 354 patients (234 Cymbalta (Duloxetine hydrochloride) , 120
placebo) were enrolled in Study 1 and a total of 520 patients (376 Cymbalta (Duloxetine hydrochloride) , 144
placebo) were enrolled in Study 2 (5% male, 95% female). Treatment with Cymbalta (Duloxetine hydrochloride)
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.
Cymbalta (Duloxetine hydrochloride) How Supplied/storage And Handling
Cymbalta (Duloxetine hydrochloride) is available as delayed release capsules in the
following strengths, colors, imprints, and presentations:
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
[see USP Controlled Room Temperature].
Cymbalta (Duloxetine hydrochloride) Patient Counseling Information
See FDA-approved
Prescribers or other health professionals should inform patients,
their families, and their caregivers about the benefits and risks associated
with treatment with Cymbalta (Duloxetine hydrochloride) and should counsel them in its appropriate use. A
patient Medication Guide About Using Antidepressants in Children and Teenagers
is available for Cymbalta (Duloxetine hydrochloride) . 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 (Duloxetine hydrochloride) .
Cymbalta (Duloxetine hydrochloride)
Cymbalta (Duloxetine hydrochloride)
Cymbalta (Duloxetine hydrochloride) Principal Display Panel
Cymbalta (Duloxetine hydrochloride)
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 (Duloxetine hydrochloride) .com
Cymbalta (Duloxetine hydrochloride)
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 (Duloxetine hydrochloride) .com
Cymbalta (Duloxetine hydrochloride)
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 (Duloxetine hydrochloride) .com
