CYMBALTA 60 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
DULOXETINE AS HYDROCHLORIDE
Available from:
ELI LILLY ISRAEL LTD
ATC code:
N06AX21
Pharmaceutical form:
GASTRO RESISTANT CAPSULES
Composition:
DULOXETINE AS HYDROCHLORIDE 60 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
LILLY S.A., SPAIN
Therapeutic group:
DULOXETINE
Therapeutic area:
DULOXETINE
Therapeutic indications:
Cymbalta is indicated for the treatment of major depressive episodes.- Cymbalta is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy.- Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD).- Cymbalta is indicated for the management of fibromyalgia.- Cymbalta is indicated for the management of chronic muscoskeletal pain when other therapies have failed or are contra-indicated. This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis.
Authorization number:
132 71 31143 00
Authorization date:
2015-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

22-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

12-04-2018

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ב הרשואש יפכ ,אתכמסאהמ (שרדנש לככ ,טמרופהו לארשיב םושירה יאנתל המאתה דבלמ) ונושלכ ץמוא ,שגומה ןולעה ןוכדע

ךיראתב

13.12.17

gastro resistant capsules

capsules

mg

30

®

Cymbalta

gastro resistant capsules

capsules

mg

60

®

Cymbalta

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-

term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use

in patients over age 25; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings

and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy monitor closely for worsening, and

for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and

communication with the prescriber. Cymbalta is not approved for use in pediatric patients [see Use in Specific Populations

(8.4)].

1

INDICATIONS AND USAGE

Cymbalta is indicated for the treatment of major depressive episodes.

- Cymbalta is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy.

- Cymbalta is indicated for the treatment of generalized anxiety disorder (GAD).

- Cymbalta is indicated for the management of fibromyalgia.

- Cymbalta is indicated for the management of chronic muscoskeletal pain when other therapies have failed or are contra-indicated.

This has been established is studies in patients with chronic low back pain (CLBP) and chronic pain due to

Osteoarthritis.

2

DOSAGE AND ADMINISTRATION

Swallow CYMBALTA whole . Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with

liquids. All of these might affect the enteric coating. Cymbalta should not be administered through a gastric tube either because the

pellets may obstruct the tube. CYMBALTA can be given without regard to meals. If a dose of CYMBALTA is missed, take the

missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the

regular time. Do not take two doses of CYMBALTA at the same time.

2.1

Dosage for Treatment of Major Depressive Disorder

Administer CYMBALTA at a total dose of 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it

may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once

daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any

additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the

need for maintenance treatment and the appropriate dose for such treatment

[see Clinical Studies (14.1)]

2.2

Dosage for treatment of Generalized Anxiety Disorder

Adult — For most patients, initiate CYMBALTA 60 mg once daily. For some patients, it may be desirable to start at 30 mg

once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily

dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a

decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The safety of doses

above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance

treatment and the appropriate dose for such treatment

[see Clinical Studies (14.2)]

Elderly — Initiate CYMBALTA at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of

60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg

once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above

120 mg once daily has not been adequately evaluated

[see Clinical Studies (14.2)]

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2.3

Dosage for treatment of Diabetic Peripheral Neuropathic Pain

Administer CYMBALTA 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit

and the higher dose is clearly less well tolerated

[see Clinical Studies (14.3)]

. For patients for whom tolerability is a concern, a lower

starting dose may be considered.

Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for

patients with renal impairment

[see Dosage and Administration (2.6), Use in Specific Populations (8.10), and Clinical Pharmacology

(12.3)]

2.4

Dosage for Treatment of Fibromyalgia

Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to the

medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses

greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated

with a higher rate of adverse reactions

[see Clinical Studies (14.4)]

2.5

Dosage for Treatment of Chronic Musculoskeletal Pain

Administer Cymbalta 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication

before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who

do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions

[see Clinical Studies

(14.5)].

2.6

Dosing in Special Populations

Hepatic Impairment – Avoid use in patients with chronic liver disease or cirrhosis

[see Warnings and Precautions (5.

) and

Use in Specific Populations (8.9)]

Severe Renal Impairment —Avoid use in patients with severe renal impairment , GFR <30 mL/min

[see Warnings and

Precautions (5.

) and Use in Specific Populations (8.10)]

2.7

Discontinuing CYMBALTA

Adverse reactions after discontinuation of CYMBALTA, after abrupt or tapered discontinuation, include: dizziness, headache,

nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather

than abrupt cessation is recommended whenever possible

[see Warnings and Precautions (5.7)]

2.8

Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of

therapy withCYMBALTA. Conversely, at least 5 days should be allowed after stopping CYMBALTA before starting an MAOI

intended to treat psychiatric disorders

[see Contraindications (4.1)]

2.9

Use of CYMBALTA with Other MAOIs such as Linezolid or Methylene Blue

Do not start CYMBALTA in a patient who is being treated with linezolid or intravenous methylene blue because there is an

increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions,

including hospitalization, should be considered [see Contraindications (4)].

In some cases, a patient already receiving CYMBALTA therapy may require urgent treatment with linezolid or intravenous

methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential

benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular

patient, CYMBALTA should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient

should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous

methylene blue, whichever comes first. Therapy with CYMBALTA may be resumed 24 hours after the last dose of linezolid or

intravenous methylene blue

[see Warnings and Precautions (5.4)]

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in

intravenous doses much lower than 1 mg/kg with CYMBALTA is unclear. The clinician should, nevertheless, be aware of the

possibility of emergent symptoms of serotonin syndrome with such use

[see Warnings and Precautions (5.4)]

3

DOSAGE FORMS AND STRENGTHS

CYMBALTA is available as delayed release capsules:

30 mg opaque white and blue capsules imprinted with “30mg” on the white body and “9543” on the blue cap

60 mg opaque green and blue capsules imprinted with “60mg” on the green body and “9542” on the blue cap

4

CONTRAINDICATIONS

Monoamine Oxidase Inhibitors (MAOIs)

-The use of MAOIs intended to treat psychiatric disorders with CYMBALTA or within 5 days of stopping treatment with

CYMBALTA is contraindicated because of an increased risk of serotonin syndrome. The use of CYMBALTA within 14 days of

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stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.8) and Warnings

and Precautions (5.4)].

Starting CYMBALTA in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also

contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.9) and Warnings and

Precautions (5.4)].

5

WARNINGS AND PRECAUTIONS

5.1

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or

the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking

antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and

certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-

standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality

in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs

increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major

depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with

antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in

adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder

(OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The

pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials

(median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of

suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences

in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs

placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in

the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range

Drug-Placebo Difference in Number of Cases of Suicidality

per 1000 Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18-24

5 additional cases

Decreases Compared to Placebo

25-64

1 fewer case

≥65

6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to

reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is

substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the

recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed

closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course

of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,

akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with

antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal

link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has

not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in

patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to

worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s

presenting symptoms.

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If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with

recognition that discontinuation can be associated with certain symptoms

[see Dosage and Administration (2.7) and Warnings and

Precautions (5.7) for descriptions of the risks of discontinuation of CYMBALTA]

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other

indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of

agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of

suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily

observation by families and caregivers. Prescriptions for CYMBALTA should be written for the smallest quantity of capsules

consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

— A major depressive episode may be the initial presentation of bipolar disorder. It

is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may

increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms

described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with

depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include

a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that

CYMBALTA is not approved for use in treating bipolar depression.

5.2

Hepatotoxicity

There have been reports of hepatic failure, sometimes fatal, in patients treated with CYMBALTA. These cases have presented

as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of

normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. CYMBALTA should be discontinued in

patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another

cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing

reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or

cirrhosis.

CYMBALTA increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver

transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of CYMBALTA-treated patients. In most patients, the

median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials in any indication, for

patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25%

(144/11,496) of CYMBALTA-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult 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.

Because it is possible that CYMBALTA and alcohol may interact to cause liver injury or that CYMBALTA may aggravate

pre-existing liver disease, CYMBALTA should not be prescribed to patients with substantial alcohol use or evidence of chronic liver

disease.

5.3

Orthostatic Hypotension, Falls and Syncope

Orthostatic hypotension, falls and syncope have been reported with therapeutic doses of CYMBALTA. Syncope

and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during

CYMBALTA treatment, particularly after dose increases.

The risk of falling appears to be related to the degree of

orthostatic decrease in blood pressure as well as other factors that may increase the underlying risk of falls.

In an analysis of patients from all placebo-controlled trials, patients treated with CYMBALTA reported a higher rate

of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in

blood pressure.

The risk of blood pressure decreases may be greater in patients taking concomitant medications

that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors

[see Warnings

and Precautions (5.12) and Drug Interactions (7.1)]

and in patients taking CYMBALTA at doses above 60 mg

daily. Consideration should be given to dose reduction or discontinuation of CYMBALTA in patients who

experience symptomatic orthostatic hypotension, falls and/or syncope during CYMBALTA therapy.

Risk of

falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily with age. As elderly

patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications,

medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences

including bone fractures and hospitalizations have been reported

[see Adverse Reactions (6.10) and Patient Counseling Information

(17)].

5.4

Serotonin Syndrome

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The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including

CYMBALTA, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants,

fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of

serotonin (in particular, MAOIs , both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous

methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium and coma),

autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular

symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea,

vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of CYMBALTA with MAOIs intended to treat psychiatric disorders is contraindicated. CYMBALTA

should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports

with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of

1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue

injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or

intravenous methylene blue in a patient taking CYMBALTA. CYMBALTA should be discontinued before initiating treatment with

the MAOI [see Dosage and Administration (2.8, 2.9), and Contraindications (4)].

If concomitant use of CYMBALTA with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl,

lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of

a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with CYMBALTA and any concomitant serotonergic agents, should be discontinued immediately if the above

events occur and supportive symptomatic treatment should be initiated.

5.5

Abnormal Bleeding

SSRIs and SNRIs, including CYMBALTA, 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 CYMBALTA and NSAIDs,

aspirin, or other drugs that affect coagulation.

5.6

Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA.

The reporting rate of SJS associated with CYMBALTA use exceeds the general population background incidence rate for this serious

skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to

underreporting.

CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of

hypersensitivity if no other etiology can be identified.

5.7

Discontinuation of Treatment with CYMBALTA

Discontinuation symptoms have been systematically evaluated in patients takingCYMBALTA. Following abrupt or tapered

discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly

higher rate in CYMBALTA-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea,

paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis and fatigue.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous

reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric

mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion,

headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting,

some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with CYMBALTA. A gradual reduction in the

dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose

or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician

may continue decreasing the dose but at a more gradual rate

[see Dosage and Administration (2.7)]

5.8

Activation of Mania/Hypomania

In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in

0.1% (4/3779) of CYMBALTA-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania

was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain 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

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effective in the treatment of major depressive disorder. As with these other agents, CYMBALTA should be used cautiously in patients

with a history of mania.

5.9 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including CYMBALTA may trigger an angle closure

attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.10 Seizures

CYMBALTA has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from

clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with

CYMBALTA and 0.01% (1/9513) of patients treated with placebo. CYMBALTA should be prescribed with care in patients with a

history of a seizure disorder.

5.11 Effect on Blood Pressure

In adult placebo-controlled clinical trials across indications from baseline to endpoint, CYMBALTA treatment was associated

with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases

of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. 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

CYMBALTA on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was

evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase

in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg

(diastolic) up to 12 hours after dosing.

Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment

[see Adverse

Reactions (6.7)]

5.12 Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for CYMBALTA metabolism.

Potential for Other Drugs to Affect CYMBALTA

CYP1A2 Inhibitors

— Co-administration of CYMBALTA with potent CYP1A2 inhibitors should be avoided

[see Drug

Interactions (7.1)]

CYP2D6 Inhibitors

— Because CYP2D6 is involved in CYMBALTA metabolism, concomitant use of CYMBALTA with

potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of CYMBALTA

[see Drug Interactions (7.2)]

Potential for CYMBALTA to Affect Other Drugs

Drugs Metabolized by CYP2D6

— Co-administration of CYMBALTA with drugs that are extensively metabolized by

CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as

nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be

approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a

TCA is co-administered with CYMBALTA. Because of the risk of serious ventricular arrhythmias and sudden death potentially

associated with elevated plasma levels of thioridazine, CYMBALTA and thioridazine should not be co-administered

[see Drug

Interactions (7.9)]

Other Clinically Important Drug Interactions

Alcohol

— Use of CYMBALTA concomitantly with heavy alcohol intake may be associated with severe liver injury. For this

reason, CYMBALTA should not be prescribed for patients with substantial alcohol use

[see Warnings and Precautions (5.2) and

Drug Interactions (7.15)]

CNS Acting Drugs

— Given the primary CNS effects of CYMBALTA, it should be used with caution when it is taken in

combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action

[see Warnings

and Precautions (5.12) and Drug Interactions (7.16)]

5.13

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including CYMBALTA. In many cases, this

hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum

sodium lower than 110 mmol/L have been reported and appeared to be reversible when CYMBALTA was discontinued. Elderly

patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are

otherwise volume depleted may be at greater risk

[see Use in Specific Populations (8.5)]

. Discontinuation of CYMBALTA should be

considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness,

and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure,

coma, respiratory arrest, and death.

5.14

Use in Patients with Concomitant Illness

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Clinical experience with CYMBALTA in patients with concomitant systemic illnesses is limited. There is no information on

the effect that alterations in gastric motility may have on the stability of CYMBALTA’s enteric coating. In extremely acidic

conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using

CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics).

CYMBALTA has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable

coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing

testing.

Hepatic Impairement – Avoid use in patients with chronic liver disease or cirrhosis

[see Dosage and Administration (2.6),

Warnings and Precautions (5.2), and Use in Specific Populations (8.9)]

Severe Renal Impairment Avoid use in patients with severe renal impairment , GFR <30 mL/min. Increased plasma

concentration of CYMBALTA, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis)

[see Dosage and Administration (2.6) and Use in Specific Populations (8.10)]

Glycemic Control in Patients with Diabetes — As observed in DPNP trials, CYMBALTA treatment worsens glycemic control

in some patients with diabetes. In three clinical trials of CYMBALTA for the management of neuropathic pain associated with

diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose

was 176 mg/dL, and the mean baseline hemoglobin A

(HbA

) was 7.8%. In the 12-week acute treatment phase of these studies,

CYMBALTA was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of

these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the CYMBALTA group and

decreased by 11.5 mg/dL in the routine care group. HbA

increased by 0.5% in the CYMBALTA and by 0.2% in the routine care

groups.

5.15

Urinary Hesitation and Retention

CYMBALTA is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during

treatment with CYMBALTA, consideration should be given to the possibility that they might be drug-related.

In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated

with CYMBALTA use, hospitalization and/or catheterization has been needed.

5.16

Laboratory Tests

No specific laboratory tests are recommended.

6

ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults

[see Boxed Warning and Warnings and

Precautions (5.1)]

Hepatotoxicity

[see Warnings and Precautions (5.2)]

Orthostatic Hypotension, Falls and Syncope

[see Warnings and Precautions (5.3)]

Serotonin Syndrome

[see Warnings and Precautions (5.4)]

Abnormal Bleeding

[see Warnings and Precautions (5.5)]

Severe Skin Reactions

[see Warnings and Precautions (5.6)]

Discontinuation of Treatment with CYMBALTA

[see Warnings and Precautions (5.7)]

Activation of Mania/Hypomania

[see Warnings and Precautions (5.8)]

Angle-Closure Glaucoma

[see Warnings and Precautions (5.9)]

Seizures

[see Warnings and Precautions (5.10)]

Effect on Blood Pressure

[see Warnings and Precautions (5.11)]

Clinically Important Drug Interactions

[see Warnings and Precautions (5.12)]

Hyponatremia

[see Warnings and Precautions (5.13)]

Urinary Hesitation and Retention [see Warnings and Precautions (5.15)]

6.1

Clinical Trial Data Sources

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.

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.

Adult - The data described below reflect exposure to CYMBALTA in placebo-controlled trials for MDD (N=3779), GAD

(N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The population studied was 17 to 89 years of age;

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65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and

CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day

[see Clinical Studies (14)]

The data below do not include results of the trial examining the efficacy of CYMBALTA in patients ≥ 65 years old for the

treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to

adverse reactions in the overall adult population.

Children and Adolescents — The data described below reflect exposure to CYMBALTA in pediatric, 10-week, placebo-

controlled trials for MDD (N=341) and GAD (N=135). The population studied (N=476) was 7 to 17 years of age with 42.4% children

age 7 to 11 years of age, 50.6% female, and 68.6% white. Patients received 30-120 mg per day during placebo-controlled acute

treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children

age 7 to 11 years of age and 51.8% female exposed to CYMBALTA in MDD and GAD clinical trials up to 36-weeks in length, in

which most patients received 30-120 mg per day.

6.2

Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Major Depressive Disorder — Approximately 8.4% (319/3779) of the patients who received CYMBALTA in placebo-

controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving

placebo. Nausea (CYMBALTA 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation

and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the CYMBALTA-treated patients and at a rate of at

least twice that of placebo).

Generalized Anxiety Disorder — Approximately 13.7% (139/1018) of the patients who received CYMBALTA in placebo-

controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767)

for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined

above) included nausea (CYMBALTA 3.3%, placebo 0.4%, and dizziness (CYMBALTA 1.3%, placebo 0.4%).

Diabetic Peripheral Neuropathic Pain — Approximately 12.9% (117/906) of the patients who received CYMBALTA in

placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo.

Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included

nausea (CYMBALTA 3.5%, placebo 0.7%), dizziness (CYMBALTA 1.2%, placebo 0.4%), and somnolence (CYMBALTA 1.1%,

placebo 0.0%).

Fibromyalgia — Approximately 17.5% (227/1294) of the patients who received CYMBALTA in 3 to 6 month placebo-

controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common

adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea

(CYMBALTA 2.0%, placebo 0.5%), headache (CYMBALTA 1.2%, placebo 0.3%), somnolence (CYMBALTA 1.1%, placebo 0.0%),

and fatigue (CYMBALTA 1.1%, placebo 0.1%).

Chronic Pain due to Osteoarthritis — Approximately 15.7% (79/503) of the patients who received CYMBALTA in 13-week,

placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508)

for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above)

included nausea (CYMBALTA 2.2%, placebo 1.0%).

Chronic Low Back Pain — Approximately 16.5% (99/600) of the patients who received CYMBALTA in 13-week, placebo-

controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common

adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea

(CYMBALTA 3.0%, placebo 0.7%), and somnolence (CYMBALTA 1.0%, placebo 0.0%).

6.3

Most Common Adult Adverse Reactions

Pooled Trials for all Approved Indications — The most commonly observed adverse reactions in CYMBALTA-treated

patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence,

constipation, decreased appetite, and hyperhidrosis.

Diabetic Peripheral Neuropathic Pain — The most commonly observed adverse reactions in CYMBALTA-treated patients (as

defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

Fibromyalgia — The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were

nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

Chronic Pain due to Osteoarthritis — The most commonly observed adverse reactions in CYMBALTA-treated patients (as

defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.

Chronic Low Back Pain — The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined

above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

6.4

Adverse Reactions Occurring at an Incidence of 5% or More Among CYMBALTA-Treated Patients in Adult Placebo-

Controlled Trials

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that

occurred in 5% or more of patients treated with CYMBALTA and with an incidence greater than placebo.

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Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled

Trials of Approved Indications

a

Percentage of Patients Reporting Reaction

Adverse Reaction

CYMBALTA

(N=8100)

Placebo

(N=5655)

Nausea

Headache

Dry mouth

Somnolence

Fatigue

Insomnia

Constipation

Dizziness

Diarrhea

Decreased appetite

Hyperhidrosis

Abdominal pain

The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed

in the table are rounded to the nearest integer.

Also includes asthenia.

Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did

not have a placebo lead-in period or dose titration.

Also includes initial insomnia, middle insomnia and early morning awakening.

Also includes hypersomnia and sedation.

Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.

6.5

Adverse Reactions Occurring at an Incidence of 2% or More Among CYMBALTA-Treated Patients in Adult Placebo-

Controlled Trials

Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD

placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with CYMBALTA and with an

incidence greater than placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD

Placebo-Controlled Trials

a,b

Percentage of Patients Reporting Reaction

System Organ Class / Adverse Reaction

CYMBALTA

(N=4797)

Placebo

(N=3303)

Cardiac Disorders

Palpitations

Eye Disorders

Vision blurred

Gastrointestinal Disorders

Nausea

Dry mouth

Constipation

Diarrhea

Abdominal pain

Vomiting

General Disorders and Administration Site Conditions

Fatigue

Metabolism and Nutrition Disorders

Decreased appetite

Nervous System Disorders

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Headache

Dizziness

Somnolence

Tremor

Psychiatric Disorders

Insomnia

Agitation

Anxiety

Reproductive System and Breast Disorders

Erectile dysfunction

Ejaculation delayed

Libido decreased

Orgasm abnormal

<1

Respiratory, Thoracic, and Mediastinal Disorders

Yawning

<1

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed

in the table are rounded to the nearest integer.

For GAD, there were no adverse events that were significantly different between treatments in adults ≥65 years that were also not

significant in the adults <65 years.

Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did

not have a placebo lead-in period or dose titration.

Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain

Also includes asthenia

Also includes hypersomnia and sedation

Also includes initial insomnia, middle insomnia and early morning awakening

Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor hyperactivity

Also includes loss of libido

Also includes anorgasmia

DPNP, FM, OA, and CLBP — Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more

of patients treated with CYMBALTA (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP

placebo-controlled trials and with an incidence greater than placebo.

Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and

CLBP Placebo-Controlled Trials

a

Percentage of Patients Reporting Reaction

System Organ Class / Adverse Reaction

CYMBALTA

(N=3303)

Placebo

(N=2352)

Gastrointestinal Disorders

Nausea

Dry Mouth

Constipation

Diarrhea

Abdominal Pain

Vomiting

Dyspepsia

General Disorders and Administration Site Conditions

Fatigue

Infections and Infestations

Nasopharyngitis

Upper Respiratory Tract Infection

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Influenza

Metabolism and Nutrition Disorders

Decreased Appetite

Musculoskeletal and Connective Tissue

Musculoskeletal Pain

Muscle Spasms

Nervous System Disorders

Headache

Somnolence

Dizziness

Paraesthesia

Tremor

<1

Psychiatric Disorders

Insomnia

Agitation

Reproductive System and Breast Disorders

Erectile Dysfunction

<1

Ejaculation Disorder

<1

Respiratory, Thoracic, and Mediastinal Disorders

Cough

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

Vascular Disorders

Flushing

Blood pressure increased

The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed

in the table are rounded to the nearest integer.

Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.

Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain

Also includes asthenia

Also includes myalgia and neck pain

Also includes hypersomnia and sedation

Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral

Also includes initial insomnia, middle insomnia, and early morning awakening .

Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity

Also includes ejaculation failure

Also includes hot flush

Also includes blood pressure diastolic increased, blood pressure systolic increased, diastolic hypertension, essential

hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary

hypertension, and systolic hypertension

6.6

Effects on Male and Female Sexual Function in Adults

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or

diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be

voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects,

was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with

CYMBALTA experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients

treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with CYMBALTA

experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience

more sexual dysfunction on CYMBALTA than on placebo as measured by ASEX total score. Negative numbers signify an

improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire

about possible sexual side effects.

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Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials

Male Patients

a

Female Patients

a

CYMBALTA

(n=175)

Placebo

(n=83)

CYMBALTA

(n=241)

Placebo

(n=126)

ASEX Total (Items 1-5)

0.56

-1.07

-1.15

-1.07

Item 1 — Sex drive

-0.07

-0.12

-0.32

-0.24

Item 2 — Arousal

0.01

-0.26

-0.21

-0.18

Item 3 — Ability to achieve erection (men);

Lubrication (women)

0.03

-0.25

-0.17

-0.18

Item 4 — Ease of reaching orgasm

0.40

-0.24

-0.09

-0.13

Item 5 — Orgasm satisfaction

0.09

-0.13

-0.11

-0.17

n=Number of patients with non-missing change score for ASEX total

p=0.013 versus placebo

p<0.001 versus placebo

6.7

Vital Sign Changes in Adults

In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, CYMBALTA treatment

was associated with mean increases of 0.23 mmHg in systolic blood pressure and 0.73 mmHg in diastolic blood pressure compared to

mean decreases of 1.09 mmHg systolic and 0.55 mmHg diastolic in placebo-treated patients. There was no significant difference in the

frequency of sustained (3 consecutive visits) elevated blood pressure

[see Warnings and Precautions (5.3 ,5.11)]

CYMBALTA treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small

increase in heart rate for change from baseline to endpoint compared to placebo of up to 137 beats per minute (increase of 1.20 beats

per minute in CYMBALTA-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).

6.8

Laboratory Changes in Adults

CYMBALTA treatment in placebo-controlled clinical trials across approved indications was associated with small mean

increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were

observed for these analytes in CYMBALTA-treated patients when compared with placebo-treated patients

[see Warnings and

Precautions (5.2)]

. High bicarbonate ,cholesterol, and abnormal (high or low) potassium, were observed more frequently in

CYMBALTA treated patients compared to placebo.

6.9

Electrocardiogram Changes in Adults

The effect of CYMBALTA 160 mg and 200 mg administered twice daily to steady state was evaluated in a

randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected.

CYMBALTA appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

6.10

Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of

CYMBALTA in Adults

Following is a list of treatment-emergent adverse reactions reported by patients treated with CYMBALTA in clinical trials. In

clinical trials of all indications, 34,756 patients were treated with CYMBALTA. Of these, 26.9% (9337) took CYMBALTA for at

least 6 months, and 12.4% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in

previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4)

which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those

occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are

those occurring in fewer than 1/1000 patients.

Cardiac Disorders

Frequent:

palpitations;

Infrequent:

myocardial infarction, tachycardia, and Takotsubo cardiomyopathy.

Ear and Labyrinth Disorders

Frequent:

vertigo;

Infrequent:

ear pain and tinnitus.

Endocrine Disorders

Infrequent:

hypothyroidism.

Eye Disorders

Frequent:

vision blurred;

Infrequent:

diplopia, dry eye, and visual impairment.

Gastrointestinal Disorders

Frequent:

flatulence;

Infrequent:

dysphagia, eructation, gastritis, gastrointestinal hemorrhage,

halitosis, and stomatitis;

Rare:

gastric ulcer.

General Disorders and Administration Site Conditions

Frequent:

chills/rigors;

Infrequent:

falls, feeling abnormal,

feeling hot and/or cold, malaise, and thirst;

Rare:

gait disturbance.

Infections and Infestations

Infrequent:

gastroenteritis and laryngitis.

Investigations

Frequent:

weight increased, weight decreased;

Infrequent:

blood cholesterol increased.

Metabolism and Nutrition Disorders

Infrequent:

dehydration and hyperlipidemia;

Rare:

dyslipidemia.

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Musculoskeletal and Connective Tissue Disorders

Frequent:

musculoskeletal pain;

Infrequent:

muscle tightness and

muscle twitching.

Nervous System Disorders

Frequent:

dysgeusia, lethargy, and paraesthesia/hypoesthesia;

Infrequent:

disturbance in

attention, dyskinesia, myoclonus, and poor quality sleep;

Rare:

dysarthria.

Psychiatric Disorders

Frequent:

abnormal dreams and sleep disorder;

Infrequent:

apathy, bruxism,

disorientation/confusional state, irritability, mood swings, and suicide attempt;

Rare:

completed suicide.

Renal and Urinary Disorders

Frequent:

urinary frequency;

Infrequent:

dysuria, micturition urgency, nocturia, polyuria,

and urine odor abnormal.

Reproductive System and Breast Disorders

Frequent:

anorgasmia/orgasm abnormal;

Infrequent:

menopausal symptoms,

sexual dysfunction, and testicular pain;

Rare

: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders

Frequent:

yawning, oropharyngal pain;

Infrequent:

throat tightness.

Skin and Subcutaneous Tissue Disorders

Frequent:

pruritus;

Infrequent:

cold sweat, dermatitis contact, erythema,

increased tendency to bruise, night sweats, and photosensitivity reaction;

Rare:

ecchymosis.

Vascular Disorders

Frequent:

hot flush;

Infrequent:

flushing, orthostatic hypotension, and peripheral coldness.

6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials

The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug

reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be

observed in pediatric patients (children and adolescents)

[see Adverse Reactions (6.5)]

. The most common (≥5% and twice placebo)

adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.

Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials

that occurred in greater than 2% of patients treated with CYMBALTA and with an incidence greater than placebo.

Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10-

week Pediatric Placebo-Controlled Trials

a

System Organ Class/Adverse Reaction

Percentage of Pediatric Patients Reporting

Reaction

CYMBALTA (N=476)

Placebo (N=362)

Gastrointestinal Disorders

Nausea

Abdominal Pain

Vomiting

Diarrhea

Dry Mouth

General Disorder and Administration Site

Conditions

Fatigue

Investigations

Decreased Weight

Metabolism and Nutrition Disorders

Decreased Appetite

Nervous System Disorder

Headache

Somnolence

Dizziness

Psychiatric Disorders

Insomnia

Respiratory, Thoracic, and Mediastinal Disorders

Oropharyngeal Pain

Cough

The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in

the table are rounded to the nearest integer.

Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.

Also includes asthenia.

Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467

CYMBALTA; N=354 Placebo).

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Also includes hypersomnia and sedation.

Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.

Other adverse reactions that occurred at an incidence of less than 2% but were reported by more CYMBALTA treated patients than

placebo treated patients and are associated CYMBALTA treatment: abnormal dreams (including nightmare), anxiety, flushing

(including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor.

Discontinuation-emergent symptoms have been reported when stopping CYMBALTA. The most commonly reported symptoms

following discontinuation of CYMBALTA in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal

pain

[see Warnings and Precautions (5.7) and Adverse Reactions (6.2)]

Growth (Height and Weight) — Decreased appetite and weight loss have been observed in association with the use of SSRIs and

SNRIs. Pediatric patients treated with CYMBALTA in clinical trials experienced a 0.1kg mean decrease in weight at 10 weeks,

compared with a mean weight gain of approximately 0.9 kg in placebo-treated patients. The proportion of patients who

experienced a clinically significant decrease in weight (≥3.5%) was greater in the CYMBALTA group than in the placebo group

(14% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, CYMBALTA-treated patients

on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-

matched peers. In studies up to 9 months, CYMBALTA-treated pediatric patients experienced an increase in height of 1.7 cm on

average (2.2 cm increase in children [7 to 11 years of age] and 1.3 cm increase in adolescents [12 to 17 years of age]). While

height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in

children [7 to 11 years of age] and increase of 0.3% in adolescents [12 to 17 years of age]). Weight and height should be

monitored regularly in children and adolescents treated with CYMBALTA.

6.12

Postmarketing Spontaneous Reports

The following adverse reactions have been identified during postapproval use of CYMBALTA. Because these reactions are

reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a

causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally related to CYMBALTA therapy and not mentioned

elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after

treatment discontinuation), angioneurotic edema, angle-closure glaucoma, cutaneous vasculitis (sometimes associated with systemic

involvement)extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia,

hypersensitivity, hypertensive crisis, colitis (microscopic or unspecified), muscle spasm, rash, restless legs syndrome, seizures upon

treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the

benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online

form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

7

DRUG INTERACTIONS

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

7.1

Inhibitors of CYP1A2

When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14)

duloxetine AUC was increased approximately 6-fold, the 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

[see Warnings and Precautions (5.12)]

7.2

Inhibitors of CYP2D6

Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of

duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would

be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine)

[see Warnings and Precautions (5.12)]

7.3

Dual Inhibition of CYP1A2 and CYP2D6

Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to

CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and C

7.4

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort

design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the

occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of

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bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered

with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg

once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged

from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC

τ,ss

max,ss

, or t

max,ss

) for both R- and S-

warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy

should be carefully monitored when duloxetine is initiated or discontinued

[see Warnings and Precautions (5.5)]

7.5

Lorazepam

Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of

duloxetine were not affected by co-administration.

7.6

Temazepam

Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine

were not affected by co-administration.

7.7

Drugs that Affect Gastric Acidity

CYMBALTA has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds

5.5. In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol.

Caution is advised in using CYMBALTA in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that

raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of CYMBALTA with

aluminum- and magnesium-containing antacids (51 mEq) or CYMBALTA with famotidine, had no significant effect on the rate or

extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administrationof

proton pump inhibitors affects duloxetine absorption

[see Warnings and Precautions (5.14)]

7.8

Drugs Metabolized by CYP1A2

In vitro

drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the

metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of

induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in

in vitro

studies, and in two clinical studies

the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered

with duloxetine (60 mg twice daily).

7.9

Drugs Metabolized by CYP2D6

Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in

conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold

[see Warnings

and Precautions (5.12)]

7.10

Drugs Metabolized by CYP2C9

Results of

in vitro

studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-

warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine

[see Drug Interactions (7.4)]

7.11

Drugs Metabolized by CYP3A

Results of

in vitro

studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or

decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or

inhibition is not anticipated, although clinical studies have not been performed.

7.12

Drugs Metabolized by CYP2C19

Results of

in vitro

studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations.

Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

7.13

Monoamine Oxidase Inhibitors (MAOIs)

[see Dosage and Administration (2.8, 2.9), Contraindications (4), and Warnings and Precautions (5.4)]

7.14

Serotonergic Drugs

[See Dosage and Administration (2.8, 2.9), Contraindications (4), and Warnings and Precautions (5.4)].

7.15

Alcohol

When CYMBALTA and ethanol were administered several hours apart so that peak concentrations of each would coincide,

CYMBALTA did not increase the impairment of mental and motor skills caused by alcohol.

In the CYMBALTA clinical trials database, three CYMBALTA-treated patients had liver injury as manifested by ALT and

total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this

may have contributed to the abnormalities seen

[see Warnings and Precautions (5.2 ,5.12)]

7.16

CNS Drugs

[See Warnings and Precautions (5.12)]

7.17

Drugs Highly Bound to Plasma Protein

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Because duloxetine is highly bound to plasma protein, administration of CYMBALTA to a patient taking another drug that is

highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However,

co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant

changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug)

[see Drug Interactions

(7.4)]

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy Category C

Risk Summary

— There are no adequate and well-controlled studies of CYMBALTA administration in pregnant women. In

animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at

oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of

120 mg/day, respectively. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at

birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD. At this dose, pup behaviors consistent with

increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-

weaning growth was not adversely affected. CYMBALTA should be used in pregnancy only if the potential benefit justifies the

potential risk to the fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reaction

— Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors

(SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged

hospitalization, respiratory support, and tube feeding which 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 the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture

is consistent with serotonin syndrome

[see Warnings and Precautions (5.4)]

Data

Animal Data— 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 (4 times the maximum recommended human dose (MRHD) of 120 mg/day on

a mg/m

basis, in rat; 7 times the MRHD in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of

10 mg/kg/day approximately equal to the MRHD in rats; 2 times the MRHD 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 (2 times the

MRHD); 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.

8.3

Nursing Mothers

Risk Summary

CYMBALTA is present in human milk . In a published study, lactating women who were weaning their infants were given

CYMBALTA. At steady state, the concentration of CYMBALTA in breast milk was approximately 25% that of matermnal plasma.

The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk

feeding should be considered along with the mother’s clinical need for CYMBALTA and any potential adverse effects on the milk-

fed child from the drug or from the underlying maternal condition. Exercise caution when CYMBALTA is administered to a nursing

woman.

Data

The disposition of CYMBALTA was studied in 6 lactating women who were at least 12 weeks postpartum. and had elected to

wean their infants. The women were given 40 mg of CYMBALTA twice daily for 3.5 days. The peak concentration measured in

breast milk occurred at a median of 3 hours after the dose. The amount of CYMBALTA in breast milk was approximately 7 mcg/day

while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day. The presence of CYMBALTA metabolites in

breast milk was not examined.

8.4

Pediatric Use

Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-

controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age. CYMBALTA

demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD

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severity score

[see Clinical Studies (14.2)]

. The safety and effectiveness in pediatric patients less than 7 years of age have not been

established.

Major Depressive Disorder - Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with

MDD, age 7to17. Neither CYMBALTA nor an active control (indicated for treatment of pediatric depression) was superior to placebo.

The safety and effectiveness in pediatric patients less than 17 years of age have not been established.

The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and

abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Perform,

regular monitoring of weight and growth in children and adolescents treated with an SNRI such asCYMBALTA

[see Adverse

Reaction (6.11)].

Animal Data - Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult)

resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly

delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood,

which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day(2 times

the MRHD, for a child) the no-effect-level was 20 mg/kg/day (≈1 times the MRHD, for a child).

8.5

Geriatric Use

Of the 2,418 patients in premarketing clinical studies of CYMBALTA for MDD, 5.9% (143) were 65 years of age or over. Of

the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing

studies, 40.5% (197) 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. In the MDD, GAD,

DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects

and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and

younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including CYMBALTA

have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse

event [see Warnings and Precautions (5.13)].

In an analysis of data from all placebo-controlled-trials, patients treated with CYMBALTA reported a higher rate of falls compared to

patients treated with placebo. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk

appears to increase steadily with age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications,

medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with CYMBALTA is

unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and

Precautions (5.3) and Adverse Reactions (6.10)].

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.

8.6

Gender

Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary.

8.7

Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not

recommended for smokers.

8.8

Race

No specific pharmacokinetic study was conducted to investigate the effects of race.

8.9

Hepatic Impairment

Patients with clinically evident hepatic impairment 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

was similar to normals in the cirrhotic patients, the half-life was about 3 times longer

[see Dosage and Administration (2.6) and

Warnings and Precautions (5.14)]

8.10

Severe Renal Impairment

Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg

dose of duloxetine, 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,

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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 impairment (estimated CrCl 30-80 mL/min) have no significant

effect on duloxetine apparent clearance

[see Dosage and Administration (2.6) and Warnings and Precautions (5.14)]

9

DRUG ABUSE AND DEPENDENCE

9.2

Abuse

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.

While CYMBALTA has not been systematically studied in humans for its potential for abuse, there was no indication of drug-

seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to

which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate

patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of CYMBLATA

(e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

9.3

Dependence

In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

10

OVERDOSAGE

10.1

Signs and Symptoms

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also

with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included

somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

10.2

Management of Overdose

There is no specific antidote to CYMBALTA, but if serotonin syndrome ensues, specific treatment (such as with

cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general

measures employed in the management of overdose with any drug.

An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored.

Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if

needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of

activated charcoal has been shown to decrease AUC and 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 and might ingest excessive quantities of a TCA. In such a case, decreased

clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend

the time needed for close medical observation

[see Warnings and Precautions (5.4) and Drug Interactions (7)]

11

DESCRIPTION

CYMBALTA® (duloxetine delayed-release capsules) 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 C

NOSHCl, 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 33.7 or 67.3 mg of duloxetine hydrochloride equivalent to 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 sucrose, hypromellose 2910 5 cps, sugar spheres, talc, hypromellose acetate succinate

(HPMCAS), triethyl citrate, and color mixture white DDB8257W.

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12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans

are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

12.2

Pharmacodynamics

Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a

less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic,

histaminergic, opioid, glutamate, and GABA receptors

in vitro

. Duloxetine does not inhibit monoamine oxidase (MAO).

CYMBALTA is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during

treatment with CYMBALTA, consideration should be given to the possibility that they might be drug-related.

12.3

Pharmacokinetics

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional

over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine

is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

Absorption and Distribution — Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag

until absorption begins (T

), with maximal plasma concentrations (C

) of duloxetine occurring 6 hours post dose. Food does not

affect the C

of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent

of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine

after an evening dose as compared to a morning dose.

The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma,

binding primarily to albumin and 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.

Metabolism and Elimination — Biotransformation and disposition of duloxetine in humans have been determined following

oral administration of

C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma,

indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine

involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the

oxidation of the naphthyl ring

in vitro

. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-

methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of

elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the

duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive

metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of

duloxetine.

Children and Adolescents (ages 7 to 17 years) — Duloxetine steady-state plasma concentration was comparable in children (7

to 12 years of age), adolescents (13 to 17 years of age) and adults. The average steady-state duloxetine concentration was

approximately 30% lower in the pediatric population (children and adolescents) relative to the adults. The model-predicted duloxetine

steady state plasma concentrations in children and adolescents were mostly within the concentration range observed in adult patients

and did not exceed the concentration range in adults.

13

NONCLINICAL TOXICOLOGY

13.1

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 (6 times the maximum recommended human dose (MRHD) 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 ( 2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to

100 mg/kg/day (4 times the MRHD).

In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36 mg/kg/day in males (3

times the MRHD) 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 (4 times the MRHD) did not alter mating or fertility.

14

CLINICAL STUDIES

The efficacy of CYMBALTA has established in the following adequate and well-controlled trials:

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Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies (14.1)].

Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults

[see Clinical Studies (14.2)]

Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults

[see Clinical Studies (14.3)]

Fibromyalgia (FM): Two trials in adults (one of 3 months duration and one of 6 months duration)

[see Clinical Studies

(14.4)]

Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-

week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies (14.5)].

14.1 Major Depressive Disorder

The efficacy of CYMBALTA as a treatment for depression was established in 4 randomized, double-blind, placebo-

controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies,

patients were randomized to CYMBALTA 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and

N=139, respectively) for 9 weeks; in the third study, patients were randomized to CYMBALTA 20 or 40 mg twice daily

(N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to CYMBALTA

40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses

greater than 60 mg/day confer additional benefits.

In all 4 studies, CYMBALTA demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton

Depression Rating Scale (HAMD-17) total score(Studies 1-4 in Table 7).

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.

Table 7: Summary of the Primary Efficacy Results for Studies in Major Depressive Disorder

Study Number

Treatment Group

Primary Efficacy Measure:HAMD-17

Mean Baseline

Score (SD)

LS Mean Change

from Baseline (SE)

Placebo-subtracted

Difference

a

(95%

CI)

Study 1

CYMBALTA (60 mg/day)

Placebo

21.5 (4.10)

21.1 (3.71)

-10.9 (0.70)

-6.1 (0.69)

-4.9 (-6.8, -2.9)

Study 2

CYMBALTA (60mg/day)

Placebo

20.3 (3.32)

20.5 (3.42)

-10.5 (0.71)

-8.3 (0.67)

-2.2 (-4.0, -0.3)

Study 3

CYMBALTA (20 mg BID)

CYMBALTA (40 mg BID)

Placebo

18.6 (5.85)

18.1 (4.52)

17.2 (5.11)

-7.4 (0.80)

-8.6 (0.81)

-5.0 (0.81)

-2.4 (-4.7, -0.2)

-3.6 (-5.9, -1.4)

Study 4

CYMBALTA (40 mg BID)

CYMBALTA (60 mg BID)

Placebo

19.9 (3.54)

20.2 (3.41)

19.9 (3.58)

-11.0 (0.49)

-12.1 (0.49)

-8.8 (0.50)

-2.2 (-3.6, -0.9)

-3.3 (-4.7, -1.9)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in

trials where multiple dose groups were included.

Difference (drug minus placebo) in least-squares mean change from baseline.

Doses statistically significantly superior to placebo.

In another study, 533 patients meeting DSM-IV criteria for MDD received CYMBALTA 60 mg once daily during an initial 12-week

open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the

following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not

meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of CYMBALTA at the same dose (N=136) or to

placebo (N=142) for 6 months. Patients on CYMBALTA experienced a statistically significantly longer time to relapse of depression

than did patients on placebo(Study 5 in Figure 1). Relapse was defined as an increase in the CGI-S score of ≥2 points compared with

that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-

week temporal criterion had to be satisfied at only the second visit. The effectiveness of CYMBALTA in hospitalized patients with

major depressive disorder has not been studied.

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD Study 5)

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14.2

Generalized Anxiety Disorder

The efficacy of CYMBALTA in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose

randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult

outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.

In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg

once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated.

One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.

The 2 flexible-dose studies involved dose titration with CYMBALTA doses ranging from 60 mg once daily to 120 mg once

daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers

at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated CYMBALTA doses of 60 mg once daily

(N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose

was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.

In all 3 studies, CYMBALTA demonstrated superiority over placebo as measured by greater improvement in the Hamilton

Anxiety Scale (HAM-A) total score (Studies 1-3 Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment

score. The SDS is a composite measurements of the extent emotional symptoms disrupt patient functioning in 3 life domains:

work/school, social life/leisure activities, and family life/home responsibilities.

In another study, 887 patients meeting DSM-IV-TR criteria for GAD received CYMBALTA 60 mg to 120 mg once daily

during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment

(defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score

no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to

continuation of CYMBALTA at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients

randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at

least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or

discontinuation due to lack of efficacy. Patients taking CYMBALTA experienced a statistically significantly longer time to relapse of

GAD than did patients taking placebo(Study 4 in Figure 2).

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

The efficacy of CYMBALTA in the treatment of patients ≥65 years of age with generalized anxiety disorder was established

in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults ≥65 years of age meeting the DSM-IV

criteria for GAD. In this study, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments

at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and

tolerability. The mean dose for patients completing the 10-week acute treatment phase was 50.95 mg. Patients treated with

CYMBALTA (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from

baseline to endpoint as measured by the Hamilton Anxiety Rating Scale total score (Study 5 in Table 8).

Table 8: Summary of the Primary Efficacy Results for Studies in General Anxiety Disorder

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Study Number

Treatment Group

Primary Efficacy Measure

Mean Baseline Score

(SD)

LS Mean Change

from Baseline (SE)

Placebo-subtracted

Difference

a

(95% CI)

Study 1 (HAM-A)

CYMBALTA (60 mg/day)

25.1 (7.18)

-12.8 (0.68)

-4.4 (-6.2, -2.5)

CYMBALTA (120 mg/day)

25.1 (7.24)

-12.5 (0.67)

-4.1 (-5.9, -2.3)

Placebo

25.8 (7.66)

-8.4 (0.67)

Study 2 (HAM-A)

CYMBALTA (60-120

mg/day)

22.5 (7.44)

-8.1 (0.70)

-2.2 (-4.2, -0.3)

Placebo

23.5 (7.91)

-5.9 (0.70)

Study 3 (HAM-A)

CYMBALTA (60-120

mg/day)

25.8 (5.66)

-11.8 (0.69)

-2.6 (-4.5, -0.7)

Placebo

25.0 (5.82)

-9.2 (0.67)

Study 5

(Elderly) (HAM-A)

CYMBALTA (60-120

mg/day)

24.6 (6.21)

-15.9 (0.63)

-4.2 (-5.9, -2.5)

Placebo

24.5 (7.05)

-11.7 (0.67)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in

trials where multiple dose groups were included.

Difference (drug minus placebo) in least squares mean change from baseline.

Dose statistically significantly superior to placebo.

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD Study 4)

14.3

Diabetic Peripheral Neuropathic Pain

The efficacy of CYMBALTA for the management of neuropathic pain associated with diabetic peripheral neuropathy was

established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral

neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-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.

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Both studies compared CYMBALTA 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared

CYMBALTA 20 mg with placebo. A total of 457 patients (342 CYMBALTA, 115 placebo) were enrolled in DPNP-1 and a total of

334 patients (226 CYMBALTA, 108 placebo) were enrolled in DPNP-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 scores from baseline. 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.

Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity -

DPNP-1

Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity -

DPNP-2

Percent Improvement in Pain from Baseline

Percentage of Patients Improved

CYM 60mg BID

CYM 60mg QD

CYM 20mg QD

Placebo

>

>

>

>

>

>

>

>

>

>

Percent Improvement in Pain from Baseline

Percentage of Patients Improved

CYM 60mg BID

CYM 60mg QD

Placebo

>

>

>

>

>

>

>

>

>

>

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14.4

Fibromyalgia

The efficacy of CYMBALTA for the management of fibromyalgia was established in two randomized, double-blind, placebo-

controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of

widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in

duration and enrolled female patients only. Study FM-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). FM-1 and FM-2 enrolled a total of

874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging

from 0 (no pain) to 10 (worse possible pain).

Both studies compared CYMBALTA 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily

dose in FM-2) with placebo. FM-2 additionally compared CYMBALTA 20 mg with placebo during the initial three months of a six-

month study. A total of 354 patients (234 CYMBALTA, 120 placebo) were enrolled in FM-1 and a total of 520 patients (376

CYMBALTA, 144 placebo) were enrolled in FM-2 (5% male, 95% female). Treatment with CYMBALTA 60 mg or 120 mg daily

statistically significantly improved the endpoint mean pain scores from baseline and increased 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 5 and 6 show the fraction of patients achieving that degree of improvement. The figures are

cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below

50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early

as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact

Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg,

and a higher dose was associated with more adverse reactions and premature discontinuations of treatment.

Figure 5: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity -

FM-1

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Figure 6: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity -

FM-2

Additionally, the benefit of up-titration in non-responders to CYMBALTA at 60 mg/day was evaluated in a separate study.

Patients were initially treated with CYMBALTA 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of

this phase were randomized to double-blind treatment with CYMBALTA at either 60 mg once daily or 120 mg once daily. Those

patients who were considered non-responders, where response was defined as at least a 30% reduction in pain score from baseline at

the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to

CYMBALTA 120 mg as compared to those who were blindly continued on CYMBALTA 60 mg.

14.5

Chronic Musculoskeletal Pain

CYMBALTA is indicated for the management of chronic musculoskeletal pain. This has been established in studies in

patients with chronic low back pain and chronic pain due to osteoarthritis.

Studies in Chronic Low Back Pain — The efficacy of CYMBALTA in chronic low back pain (CLBP) was assessed in two

double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-

weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of CYMBALTA in the treatment of chronic low back pain.

Patients in all studies had no signs of radiculopathy or spinal stenosis.

Study CLBP-1

: Two hundred thirty-six adult patients (N=115 on CYMBALTA, N=121 on placebo) enrolled and 182 (77%)

completed 13-week treatment phase. After 7 weeks of treatment, CYMBALTA patients with less than 30% reduction in average daily

pain and who were able to tolerate duloxetine 60 mg once daily had their dose of CYMBALTA, in a double-blinded fashion, increased

to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging

from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA 60-120 mg daily had a

significantly greater pain reduction compared to placebo. Randomization was stratified by the patients’ baseline NSAIDs-use status.

Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study CLBP-2

: Four hundred and four patients were randomized to receive fixed doses of CYMBALTA daily or a matching

placebo (N=59 on CYMBALTA 20 mg, N=116 on CYMBALTA 60 mg, N=112 on CYMBALTA 120 mg, N=117 on placebo) and

267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three CYMBALTA doses showed a

statistically significant difference in pain reduction compared to placebo.

Study CLBP-3

: Four hundred and one patients were randomized to receive fixed doses of CYMBALTA 60 mg daily or

placebo (N=198 on Cymbalta, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain rating of 6

on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking

Cymbalta 60 mg daily had significantly greater pain reduction compared to placebo.

For various degrees of improvement in pain from baseline to study endpoint, Figures 7 and 8 show the fraction of patients in

CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline

X CYMBCP A 14

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is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were

assigned the value of 0% improvement.

Figure 7: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity –

CLBP-1

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Figure 8: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity –

CLBP-3

Studies in Chronic Pain Due to Osteoarthritis — The efficacy of CYMBALTA in chronic pain due to osteoarthritis was

assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All

patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee.

Randomization was stratified by the patients’ baseline NSAIDs-use status. Patients assigned to CYMBALTA started treatment in both

studies at a dose of 30 mg once daily for one week. After the first week, the dose of CYMBALTA was increased to 60 mg once daily.

After 7 weeks of treatment with CYMBALTA 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain

reduction) and tolerated CYMBALTA 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients,

regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving CYMBALTA 60 mg once

daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both

studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-

week data from the combined CYMBALTA 60 mg and 120 mg once daily treatment groups compared to the placebo group.

Study OA-1

: Two hundred fifty-six patients (N=128 on CYMBALTA, N=128 on placebo) enrolled and 204 (80%) completed

the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible

pain). After 13 weeks of treatment, patients taking CYMBALTA had significantly greater pain reduction. Subgroup analyses did not

indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study OA-2

: Two hundred thirty-one patients (N=111 on Cymbalta, N=120 on placebo) enrolled and 173 (75%) completed the

study. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13

weeks of treatment, patients taking Cymbalta did not show a significantly greater pain reduction.

In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of

patients achieving that degree of improvement. The figure is 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 the value of

0% improvement.

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Figure 9: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity –

OA-1

16

HOW SUPPLIED/STORAGE AND HANDLING

16.1

How Supplied

CYMBALTA is available as delayed release capsules in the following strengths, colors, imprints, and presentations:

Features

Strengths

30 mg

a

60 mg

a

Body color

Opaque white

Opaque green

Cap color

Opaque blue

Opaque blue

Cap imprint

9543

9542

Body imprint

30mg

60mg

Capsule number

PU3240

PU3237

equivalent to duloxetine base

16.2

Storage

Do not store above 25°C.

Manufacturer:

Lilly S.A., Spain

License Holder:

Eli Lilly Israel Ltd., POB 2160, Herzliya 46120

The content of this leaflet was approved by the Ministry of Health in February 2017, and updated according to the guidelines of the

Ministry of Health in January 2018.

X CYMBCP A 14

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

.102.50

.102.50

.102.50

ךיראת

:

Sep2016

5

1

תילגנאב רישכת םש

םושירה רפסמו

:

Cymbalta 30 mg

:םושיר 'סמ ,

321072333177231

Cymbalta 60 mg

:םושיר 'סמ ,

321032333277231

םושירה לעב םש

:

Eli Lilly Israel Ltd.

טורפל דעוימ הז ספוט

דבלב תורמחה

:אפורל ןולע

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Adverse events

תפסות

6 ADVERSE REACTIONS

6.12 Postmarketing Spontaneous Reports

…Acute pancreatitis

:ןכרצל ןולע

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

:יאוול תועפות

תפסות

יאוול תועפות

העודי יתלב תוחיכשב יאוול תועפות

הפירח בלבל תקלד

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