Adverse reactions : תופעות לוואי

4.8 Undesirable effects

The undesirable effects observed during treatment with Milnacipran in depression indication are observed mainly during the first week or first two weeks of treatment and subsequently regress, concomitantly with improvement in the depressive episode.
The following table gives the adverse events for which a causality assessment was not ‘excluded’, observed in 13 clinical studies, including 5 placebo-controlled clinical trials (comprising a total of 3,059 subjects - 2,557 on milnacipran and 502 on placebo) in depressive patients.
The most commonly reported adverse drug reactions in depressive patients treated with Milnacipran in the clinical trials were nausea, and headaches.

Table of adverse reactions for depression
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). No adverse drug reaction are ‘very rare’ in frequency and therefore the column ‘very rare’ is not represented in the table.

Very common (≥     Common (≥ 1/100 to Uncommon (≥          Rare (≥ 1/10,000 to    Not known 1/10)              <1/10)             1/1,000 to <1/100)   <1/1,000)
Blood and lymphatic system disorders
Ecchymosis(1)(3)
Cutaneous or mucous bleedings(1)(3)
Immune system disorders
Hypersensitivity    Anaphylactic shock
Endocrine disorders
Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
Hyperlipidaemia                            hyponatremia(1)(3)
Weight decreased
Psychiatric disorders

Agitation            Panic attack        Derealization        Aggression Anxiety              Confusional state   thinking abnormal
Depression           Delusion            Psychotic disorder
Hallucinations.
Eating disorders     Mania
Sleep disorders      Libido decreased
Suicidal behaviour   Nightmare
Suicidal ideation


Nervous system disorders
Headaches         Migraine                Memory impairment   Cerebrovascular      Serotonin Tremor                  Akathisia           accident             syndrome (1)(*) Dizziness-              Balance disorder-   Dyskinesia-          Convulsion (1)(2) Dysesthesia             Dysgeusia           Parkinsonism
Somnolence              Syncope             Convulsion
Eye disorders

Dry eye-Eye pain
Mydriasis
Accommodation disorders-Vision blurred visual impairment
Ear and labyrinth disorders
Tinnitus-
Vertigo
Cardiac disorders
Tachycardia          Arrhythmia-         Angina pectoris      Takotsubo Palpitations         Bundle branch                            cardiomyopathy block
Extrasystoles
Myocardial infarction

Vascular disorders
Hot flush            Raynaud’s
Hypertension         phenomenon
Hypotension-
Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders
Cough-
Dyspnoea
Nasal dryness
Pharyngeal disorder
Gastrointestinal disorders
    Nausea             Constipation-         Colitis -
Diarrhoea             Gastritis
Abdominal pain-       Gastrointestinal
Dyspepsia             motility disorders
Vomiting              Abdominal
Dry mouth             discomfort
Abdominal distension
Gastroduodenal ulcer
Haemorrhoids
Stomatitis

Hepatobiliary disorders
Hepatic enzyme       Hepatitis -             cytolytic hepatitis (1) increased            Hepatocellular injury
Skin and subcutaneous tissue disorders
Pruritus -          Urticaria               Photosensitivity        Stevens-Johnson Rash                Dermatitis -            reaction                syndrome Hyperhidrosis       Dermatosis
Musculoskeletal and connective tissue disorders
Musculoskeletal pain Muscle rigidity
Myalgia
Renal and urinary disorders
Dysuria -             Chromaturia -
Pollakiuria           Urinary incontinence
Urinary retention
Reproductive system and breast disorders
Ejaculation disorders Amenorrhea                                   Postpartum Erectile dysfunction Menorrhagia                                   haemorrhage(**) Testicular pain       Menstrual disorder
Metrorrhagia
Prostatic disorder
General disorders and administration site conditions
Fatigue              Pyrexia
Chest pain -
Chills
Feeling abnormal -
Malaise

(1)
Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in placebo-controlled clinical trials.
(2)
Observed especially in patients with past history of epilepsy
(3) see section 4.4.
(*) A serotonin syndrome, particularly when milnacipran medication is combined with other agents (see section 4.5), characterised by at least three symptoms including changes in psychiatric state and behaviour (excitement, confusion, anxiety, agitation, delirium and restlessness), motor dysfunction (tremor, rigidity, myoclonus, hyperreflexia, and ataxia), hypotension or hypertension and autonomic symptoms such as sweating, fever, shivering and diarrhoea may occur.


(**) This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).
Cases of suicidal behaviour and suicidal ideations have been reported during Milnacipran therapy or early after treatment discontinuation (see section 4.4).

Withdrawal syndrome
A few cases of potential withdrawal reactions were reported after Milnacipran treatment discontinuation. Generally, for SSRIs and SNRIs, the symptoms are mild to moderate and self- limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when Milnacipran treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 and 4.4).

Additional reactions reported from post-marketing experience in depression indication (frequency not known)
Some other adverse reactions reported during the post-marketing experience in depressed patients were related to the depressive illness:
• elimination of psychomotor inhibition, with suicidal risk
• mood switch with episodes of mania
• reactivation of a delusion in psychotic patients
• paroxysmal manifestations of anxiety (for psychostimulant antidepressants) 
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.