Special Warning : אזהרת שימוש

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 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 
There were suicides in the adult CYMBALTA trials, but the number was not sufficient to reach any conclusion about CYMBALTA effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.8) 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 (ULN)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, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the (ULN)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 CYMBALTA dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, 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 in patients treated with the recommended CYMBALTA dosages. 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 (BP) 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 BP. The risk of BP 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 geriatric 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 fractures and hospitalizations have been reported with CYMBALTA use [see Adverse Reactions (6.1)].

5.4     Serotonin Syndrome
Serotonin-norepinephrine reuptake inhibitors (SNRIs), including CYMBALTA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.13)]. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of CYMBALTA with MAOIs is contraindicated. In addition, do not initiate CYMBALTA in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking CYMBALTA, discontinue CYMBALTA before initiating treatment with the MAOI [see Contraindications (4) and Drug Interactions (7.13)].

Monitor all patients taking CYMBALTA for the emergence of serotonin syndrome. Discontinue treatment with CYMBALTA and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of CYMBALTA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.5      Increased Risk of Bleeding
Drugs that interfere with serotonin reuptake inhibition, including CYMBALTA, may increase the risk of bleeding events.
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. A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking CYMBALTA . Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk .Inform patients about the risk of increased bleeding associated with the concomitant use of CYMBALTA and NSAIDs, aspirin, or other drugs that affect coagulation[see Drug Interactions (7.4)].

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 Syndrome
Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. 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 healthcare provider may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.8)].

5.8    Activation of Mania/Hypomania
In adult placebo-controlled trials in patients with MDD, 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 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     Increases in Blood Pressure
In adult placebo-controlled clinical trials across the approved adult populations 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 ( approximately 3.3 times the maximum recommended dosage ). 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 (6.1)].

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 Contraindications (4) and 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 with CYMBALTA use and appeared to be reversible when CYMBALTA was discontinued. Geriatric 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
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 Impairment
Avoid use in patients with chronic liver disease or cirrhosis [see Dosage and Administration (2.7), Contraindications (4), 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/minute Increased plasma concentration of CYMBALTA, and especially of its metabolites, occurred in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.7), Contraindications (4), and Use in Specific Populations (8.10)].

Glycemic Control in Patients with Diabetes

As observed in DPNP trials, CYMBALTA treatment worsened glycemic control in some patients with diabetes. In three clinical trials of CYMBALTA for the management of neuropathic pain associated with diabetic peripheral neuropathy [see Clinical Studies (14.4)], the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, CYMBALTA was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the CYMBALTA group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the CYMBALTA group and by 0.2% in the routine care group.


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 Sexual Dysfunction
Use of SNRIs, including CYMBALTA, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of CYMBALTA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.
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)]
• Increased Risk of Bleeding [see Warnings and Precautions (5.5)]
• Severe Skin Reactions [see Warnings and Precautions (5.6)]
• Discontinuation Syndrome [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)]
• Increases in 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)] • Sexual Dysfunction [see Warnings and Precautions (5.16)]

6.1     Clinical Trials Experience
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 patients who experienced, at least once, one 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.

Adverse Reactions in Adults
Adult Clinical Trial Database
The data described below reflect exposure to CYMBALTA in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age; In this pooled population, 66%,61%,61%,43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations , respectively. Most patients received CYMBALTA dosages of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The data below do not include results of the trial that evaluated the efficacy of CYMBALTA for the treatment of GAD in patients ≥65 years old (Study GAD -5) [See Clinical Studies (14.3]; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population.

Adverse Reactions leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder
Approximately 8.4% (319/3779) of CYMBALTA -treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo -treated patients. Nausea (CYMBALTA 1.1%, placebo 0.4%) was the only 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 -treated patients).

Generalized Anxiety Disorder
Approximately 13.7% (139/1018) of the CYMBALTA -treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo treated patients . 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 CYMBALTA -treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo-treated patients . 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%).

Fibromyalgia
Approximately 17.5% (227/1294) of the CYMBALTA -treated patients in 3 to 6 month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo treated patients .
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%), and fatigue (CYMBALTA 1.1%, placebo 0.1%).

Chronic Pain due to Osteoarthritis
Approximately 15.7% (79/503) of the CYMBALTA -treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo treated patients . Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 2.2%, placebo 1%).

Chronic Low Back Pain
Approximately 16.5% (99/600) of the CYMBALTA -treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo treated 
patients.Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (CYMBALTA 3%, placebo 0.7%), and somnolence (CYMBALTA 1%, placebo 0%).

Most Common Adverse Reactions in Adult Trials
The most commonly observed adverse reactions in CYMBALTA-treated patients (as defined above) were: • Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.
• Fibromyalgia :nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.
• Chronic Pain due to Osteoarthritis :nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.
• Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

The most commonly observed adverse reactions in CYMBALTA-treated patients in all the pooled adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved adult populations (i.e MDD, GAD, DPNP, FM,OA and CLBP ) that occurred in 5% or more of CYMBALTA-treated patients and with an incidence greater than placebo- treated patients.

Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations a
Percentage of Patients Reporting Reaction
Adverse Reaction                               CYMBALTA                                Placebo (N=8100)                             (N=5655)
Nauseac                                             23                                     8 Headache                                            14                                    12 Dry mouth                                           13                                     5 e
Somnolence                                          10                                     3 Fatigueb,c                                           9                                     5 Insomniad                                            9                                     5 c
Constipation                                         9                                     4 Dizzinessc                                           9                                     5 Diarrhea                                             9                                     6 Decreased appetitec                                  7                                     2 c
Hyperhidrosis                                        6                                     1 Abdominal painf                                      5                                     4 a Includes adults with MDD ,GAD ,DPNP, FM and chronic musculoskeletal 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.
b   Also includes asthenia.
c   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.
d   Also includes initial insomnia, middle insomnia and early morning awakening.
e   Also includes hypersomnia and sedation.
f   Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.


Adverse Reactions in Pooled MDD and GAD Trials in Adults
Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of CYMBALTA - treated patients and with an incidence greater than placebo treated patients .


Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo- Controlled Trials in Adultsa b

                                                                                 Percentage of Patients Reporting Reaction
System Organ Class / Adverse Reaction                                       CYMBALTA                         Placebo (N=4797)                      (N=3303)
Cardiac Disorders
Palpitations                                                                        2                                       1 Eye Disorders
Vision blurred                                                                      3                                       1 Gastrointestinal Disorders
Nauseac                                                                            23                                       8 Dry mouth                                                                          14                                       6 Constipationc                                                                       9                                       4 Diarrhea                                                                            9                                       6 Abdominal paind                                                                     5                                       4 Vomiting                                                                            4                                       2 General Disorders and Administration Site
Conditions
Fatiguee                                                                            9                                       5 Metabolism and Nutrition Disorders
Decreased appetitec                                                                 6                                       2 Nervous System Disorders
Headache                                                                           14                                       14 Dizzinessc                                                                          9                                       5 Somnolencef                                                                         9                                       3 Tremor                                                                              3                                       1 Psychiatric Disorders
Insomniag                                                                           9                                       5 Agitationh                                                                          4                                       2 Anxiety                                                                             3                                       2 Reproductive System and Breast Disorders
Erectile dysfunction                                                                4                                       1 Ejaculation delayedc                                                                2                                       1 Libido decreasedi                                                                   3                                       1 Orgasm abnormalj                                                                    2                                       <1 Respiratory, Thoracic, and Mediastinal
Disorders
Yawning                                                                             2                                       <1 Skin and Subcutaneous Tissue Disorders
Hyperhidrosis                                                                       6                                       2 a
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.
b For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years.
c 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.
d includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain e includes asthenia f includes hypersomnia and sedation g includes initial insomnia, middle insomnia and early morning awakening h includes feeling jittery, nervousness, restlessness, tension, and psychomotor hyperactivity i includes loss of libido j includes anorgasmia


Adverse reactions in the DPNP, FM, OA, and CLBP Adult trials


Table 4 gives displays the incidence of adverse reactions that occurred in 2% or more of CYMBALTA -treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients .

Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trialsa
Percentage of Patients Reporting Reaction
System Organ Class / Adverse Reaction                       CYMBALTA                          Placebo (N=3303)                       (N=2352)
Gastrointestinal Disorders
Nausea                                                            23                             7 Dry Mouthb                                                        11                             3 Constipationb                                                     10                             3 Diarrhea                                                           9                             5 Abdominal Painc                                                    5                             4 Vomiting                                                           3                             2 Dyspepsia                                                          2                             1 General Disorders and Administration Site
Conditions
Fatigued                                                          11                             5 Infections and Infestations
Nasopharyngitis                                                    4                             4 Upper Respiratory Tract Infection                                  3                             3 Influenza                                                          2                             2 Metabolism and Nutrition Disorders
Decreased Appetiteb                                                8                             1 Musculoskeletal and Connective Tissue
Musculoskeletal Paine                                              3                             3 Muscle Spasms                                                      2                             2 Nervous System Disorders
Headache                                                          13                             8 b,f
Somnolence                                                        11                             3 Dizziness                                                          9                             5 Paraesthesiag                                                      2                             2 Tremorb                                                            2                            <1 Psychiatric Disorders
Insomniab,h                                                       10                             5 i
Agitation                                                          3                             1 Reproductive System and Breast Disorders
Erectile Dysfunctionb                                              4                            <1 Ejaculation Disorderj                                              2                            <1 Respiratory, Thoracic, and Mediastinal Disorders
Cough                                                              2                             2 Skin and Subcutaneous Tissue Disorders
Hyperhidrosis                                                      6                             1 Vascular Disorders
Flushingk                                                          3                             1 l
Blood pressure increased                                           2                             1 a   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.
b   Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.
c   includes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness and gastrointestinal pain d   includes asthenia

 e  includes myalgia and neck pain f includes hypersomnia and sedation g includes hypoaesthesia, facial hypoaesthesia, genital hypoaesthesia and oral paraesthesia h includes initial insomnia, middle insomnia, and early morning awakening .
i   includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity j includes ejaculation failure k includes hot flush l includes increased diastolic blood pressure, increased systolic , blood pressure, diastolic hypertension, essential  hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension 

Effects on Male and Female Sexual Function in Adults with MDD
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 adverse reactions , was used prospectively in 4 MDD placebo-controlled adult trials (studies MDD-1, MDD-2 ,MDD-3 and MDD-4) [see Clinical Studies (14.2)].The ASEX, scale include five questions that pertain to the following aspects of sexual function : 1) sex drive, 2) ease of arousal, 3)ability to achieve erection (men) or lubrication (women),4) ease of reaching orgasm and 5) orgasm satisfaction .Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients.

In these trials, CYMBALTA-treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5). CYMBALTA- treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in CYMBALTA- treated patients.
Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials Male Patientsa              Female Patientsa
CYMBALTA            Placebo CYMBALTA            Placebo
(n=175)            (n=83)    (n=241)          (n=126)
ASEX Total (Items 1-5)                         0.56b              -1.07     -1.15             -1.07 Item 1 — Sex drive                             -0.07              -0.12     -0.32             -0.24 Item 2 — Arousal                                0.01              -0.26     -0.21             -0.18 Item 3 — Ability to achieve erection (men);     0.03              -0.25     -0.17             -0.18 Lubrication (women)
Item 4 — Ease of reaching orgasm                0.40c             -0.24     -0.09             -0.13 Item 5 — Orgasm satisfaction                    0.09              -0.13     -0.11             -0.17 a   n=Number of patients with non-missing change score for ASEX total b   p=0.013 versus placebo c   p<0.001 versus placebo


Vital Sign Changes in Adults
In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, CYMBALTA treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP 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 adult populations typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 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).


Laboratory Changes in Adults
CYMBALTA treatment in placebo-controlled clinical trials across approved adult populations 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 -treated patients.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of CYMBALTA in Adults Following is a list of adverse reactions reported by patients treated with CYMBALTA in clinical adult trials. In clinical trials of all approved adult populations ,34,756 patients were treated with CYMBALTA. Of these, 27% (9337) took CYMBALTA for at least 6 months, and 12% (4317) took CYMBALTA 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.
• 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, oropharyngeal 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.

6.2     Postmarketing Experience
The following adverse reactions have been identified during post approval 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, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, 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 https://sideeffects.health.gov.il

Effects on Driving