A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cymbalta Warnings, Precautions, Pregnancy, Nursing, Abuse - Duloxetine Hcl
Cymbalta Warnings, Precautions, Pregnancy, Nursing, Abuse - Duloxetine Hcl
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder, both adult and pediatric,
may experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality), whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Although
there has been a long-standing concern that antidepressants may have a role
in inducing worsening of depression and the emergence of suicidality in certain
patients, a causal role for antidepressants in inducing such behaviors has not
been established. Nevertheless, patients being treated with antidepressants
should be observed closely for clinical worsening and suicidality, especially
at the beginning of a course of drug therapy, or at the time of dose changes,
either increases or decreases. Consideration should be given to changing
the therapeutic regimen, including possibly discontinuing the medication, in
patients whose depression is persistently worse or whose emergent suicidality
is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.
Because of the possibility of co-morbidity between major depressive
disorder and other psychiatric and nonpsychiatric disorders, the same precautions
observed when treating patients with major depressive disorder should be observed
when treating patients with other psychiatric and nonpsychiatric disorders.
The following symptoms - anxiety, agitation, panic attacks,
insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania - have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric. Although
a causal link between the emergence of such symptoms and either the worsening
of depression and/or the emergence of suicidal impulses has not been established,
consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients for whom such symptoms are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants
for major depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of agitation,
irritability, and the other symptoms described above, as well as the emergence
of suicidality, and to report such symptoms immediately to health care providers.
Prescriptions for Cymbalta should be written for the smallest quantity of capsules
consistent with good patient management, in order to reduce the risk of overdose.
If the decision has been made to discontinue treatment, medication
should be tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can be associated with certain symptoms (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION,
Discontinuing Cymbalta, for a description of the risks of discontinuation of
Cymbalta).
A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a mixed/manic episode in patients at risk
for bipolar disorder. Whether any of the symptoms described above represent
such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that Cymbalta is not approved for use in treating bipolar
depression.
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.
PRECAUTIONS
General
Hepatotoxicity
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.
The combination of transaminase elevations and elevated bilirubin,
without evidence of obstruction, is generally recognized as an important predictor
of severe liver injury. 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. Because it
is possible that duloxetine and alcohol may interact to cause liver injury,
Cymbalta should ordinarily not be prescribed to patients with substantial alcohol
use.
Effect on Blood Pressure
In MDD clinical trials, Cymbalta treatment was associated with
mean increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic
and an increase in the incidence of at least one measurement of systolic blood
pressure over 140 mm Hg compared to placebo.
Blood pressure should be measured prior to initiating treatment
and periodically measured throughout treatment (see ADVERSE
REACTIONS, Vital Sign Changes).
Activation of Mania/Hypomania
In placebo-controlled trials in patients with major depressive
disorder, activation of mania or hypomania was reported in 0.1% (1/1139) of
Cymbalta-treated patients and 0.1% (1/777) of placebo-treated patients. Activation
of mania/hypomania has been reported in a small proportion of patients with
mood disorders who were treated with other marketed drugs effective in the treatment
of major depressive disorder. As with these other agents, Cymbalta should be
used cautiously in patients with a history of mania.
Seizures
Cymbalta has not been systematically evaluated in patients
with a seizure disorder, and such patients were excluded from clinical studies.
In placebo-controlled clinical trials in patients with major depressive disorder,
seizures occurred in 0.1% (1/1139) of patients treated with Cymbalta and 0%
(0/777) of patients treated with placebo. In placebo-controlled clinical trials
in patients with diabetic peripheral neuropathy, seizures did not occur in any
patients treated with either Cymbalta or placebo. Cymbalta should be prescribed
with care in patients with a history of a seizure disorder.
Controlled Narrow-Angle Glaucoma
In clinical trials, Cymbalta was associated with an increased
risk of mydriasis; therefore, it should be used cautiously in patients with
controlled narrow-angle glaucoma (see CONTRAINDICATIONS,
Uncontrolled Narrow-Angle Glaucoma).
Discontinuation of Treatment with Cymbalta
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.
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).
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.
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).
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 ADVERSE REACTIONS, Electrocardiogram
Changes).
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 ADVERSE REACTIONS, Electrocardiogram
Changes).
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.
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 CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION).
Markedly increased exposure to duloxetine occurs in patients
with hepatic insufficiency and Cymbalta should not be administered to these
patients (see CLINICAL PHARMACOLOGY
and DOSAGE AND ADMINISTRATION).
Information for Patients
Physicians are advised to discuss the following issues with
patients for whom they prescribe Cymbalta.
Patients and their families should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, impulsivity, akathisia, hypomania, mania, worsening of depression,
and suicidal ideation, especially early during antidepressant treatment. Such
symptoms should be reported to the patient’s physician, especially if they are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
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.
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. 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.
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.
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.
Patients should be advised to notify their physician if they
become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they
are breast-feeding.
While patients with MDD may notice improvement with Cymbalta
therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
Laboratory Tests
No specific laboratory tests are recommended.
Carcinogenesis, Mutagenesis, 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.
Pregnancy
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,
Monoamine Oxidase Inhibitors). When treating a pregnant woman with Cymbalta
during the third trimester, the physician should carefully consider the potential
risks and benefits of treatment (see DOSAGE
AND ADMINISTRATION).
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.
Nursing Mothers
Duloxetine and/or its metabolites are excreted into the milk
of lactating rats. It is unknown whether or not duloxetine and/or its metabolites
are excreted into human milk, but nursing while on Cymbalta is not recommended.
Pediatric Use
Safety and efficacy in pediatric patients have not been established
(see WARNINGS, Clinical Worsening
and Suicide Risk).
Geriatric Use
Of the 2418 patients in clinical studies of Cymbalta for MDD,
5.9% (143) were 65 years of age or over. Of the 1074 patients in the DPN studies,
33% (357) were 65 years of age or over. 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.
top
