Adverse reactions : תופעות לוואי

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