Adverse reactions : תופעות לוואי

4.8     Undesirable effects
 a. Summary of the safety profile

The most commonly reported adverse events in patients treated with YENTREVE in clinical trials in SUI and other lower urinary tract disorders were nausea, dry mouth, fatigue and constipation. The data analysis of four 12-week, placebo-controlled clinical trials in patients with SUI, including 958 duloxetine-treated and 955 placebo-treated patients, showed that the onset of the reported adverse events typically occurred in the first week of therapy. However, the majority of the most frequent adverse events were mild to moderate and resolved within 30 days of occurrence (e.g. nausea).
 b. Tabulated summary of adverse reactions
Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo- controlled clinical trials.

Table 1: Adverse reactions
Frequency estimate: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very           Common            Uncommon                Rare           Very rare         Not known common
Infections and infestations
Laryngitis
Immune system disorders
Hyper-              Anaphylactic sensitivity         reaction disorder
Endocrine disorders
Hypo-thyroidism
Metabolism and nutrition disorders
Appetite           Dehydration     Hyperglycemia decreased                          (reported especially in diabetic patients)
Hyponatremia
SIADH6

Psychiatric disorders


Very            Common         Uncommon             Rare        Very rare     Not known common
Insomnia         Bruxism          Suicidal
Agitation        Disorientation   behaviour5,6
Libido           Apathy           Suicidal decreased        Orgasm           ideation5,7
Anxiety          abnormal         Mania6
Sleep disorder   Abnormal         Hallucinations dreams           Aggression and anger4,6


Nervous system disorders
Headache           Nervousness      Serotonin
Dizziness          Disturbance in   syndrome6
Lethargy           attention        Convulsions1,6
Somnolence         Dysgeusia        Myoclonus
Tremor             Poor quality     Akathisia6
Paraesthesia       sleep            Psychomotor restlessness6
Extra-pyramidal symptoms6
Dyskinesia
Restless legs syndrome
Eye disorders
Blurred vision   Mydriasis        Glaucoma
Visual impairment
Dry eye
Ear and labyrinth disorders
Vertigo           Tinnitus1
Ear pain
Cardiac disorders
Palpitations     Supra-                        Stress
Tachycardia      ventricular                   cardiomyopathy arrhythmia,                   (Takotsubo mainly atrial                 cardiomyopathy) fibrillation6
Vascular disorders
Hypertension3,7   Syncope2         Hypertensive
Flushing          Blood pressure   crisis3 increase3        Orthostatic hypotension2
Peripheral coldness
Respiratory, thoracic and mediastinal disorders


Very          Common          Uncommon               Rare           Very rare   Not known common
Yawning            Throat tightness
Epistaxis
Interstitial lung disease10
Eosinophilic pneumonia6
Gastrointestinal disorders
Nausea         Diarrhoea        Gastrointestinal   Haematochezia
Dry mouth      Abdominal        haemorrhage7       Microscopic
Constipation pain               Gastroenteritis    colitis9
Vomiting         Stomatitis
Dyspepsia        Eructation
Gastritis
Dysphagia
Flatulence
Breath odour
Hepato-biliary disorders
Hepatitis3        Hepatic failure6
Elevated liver    Jaundice6 enzymes (ALT,
AST, alkaline phosphatase)
Acute liver injury
Skin and subcutaneous tissue disorders
Sweating          Rash              Stevens-            Cutaneous increased         Night sweats      Johnson             vasculitis
Urticaria         Syndrome6
Dermatitis        Angio-neurotic contact Cold      oedema6 sweat
Increased         Photo- tendency to       sensitivity bruise            reactions

Musculoskeletal and connective tissue disorders
Musculo-skeletal Muscle pain             twitching
Muscle spasm
Muscle tightness
Trismus
Renal and urinary disorders


Very           Common             Uncommon                  Rare             Very rare           Not known common
Urinary                    Urinary hesitation                 retention6
Dysuria                    Polyuria
Nocturia                   Urine flow
Pollakiuria                decreased
Urine odour abnormal
Reproductive system and breast disorders
Gynaecological             Menstrual haemorrhage                disorder
Menopausal                 Galactorrhoea symptoms                   Hyperprolactina emia
Postpartum haemorrhage6
General disorders and administration site conditions
Fatigue        Asthenia         Chest pain7          Gait disturbance Chills           Falls8
Feeling abnormal
Feeling cold
Thirst
Malaise
Feeling hot

Investigations
Weight decrease       Blood
Weight increase       potassium
Blood                 increased cholesterol increased
Blood creatine phosphokinase increased
1
Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.
2
Cases of orthostatic hypotension and syncope have been reported especially at the initiation of treatment.
3
See section 4.4
4
Cases of aggression and anger have been reported particularly early in treatment or after treatment discontinuation.
5
Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or early after treatment discontinuation (see section 4.4).
6
Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo- controlled clinical trials.
7
Not statistically significantly different from placebo.
8
Falls were more common in the elderly (≥65 years old).
9
Estimated frequency based on all clinical trial data.
10
Estimated frequency based on placebo-controlled clinical trials.


c. Description of selected adverse reactions
Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence, agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea, hyperhydrosis and vertigo are the most commonly reported reactions.

Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTcB measurements between duloxetine-treated and placebo-treated patients.

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-treated patients. HbA1c was stable in both duloxetine-treated and placebo- treated patients. In the extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-treated group. There was also a small increase in fasting blood glucose and in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care group.

Reporting of suspected adverse reactions
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/