Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Depressed patients display a number of symptoms that are associated with the illness itself.
It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with mirtazapine.

The most commonly reported adverse reactions, occurring in more than 5% of patients treated with mirtazapine in randomized placebo-controlled trials (see below) are somnolence, sedation, dry mouth, weight increased, increase in appetite, dizziness and fatigue.

All randomized placebo-controlled trials in patients (including indications other than major depressive disorder), have been evaluated for adverse reactions of mirtazapine. The meta- analysis considered 20 trials, with a planned duration of treatment up to 12 weeks, with 1,501 patients (134 person years) receiving doses of mirtazapine up to 60 mg and 850 patients (79 person years) receiving placebo. Extension phases of these trials have been excluded to maintain comparability to placebo treatment.

Table 1 shows the categorized incidence of the adverse reactions, which occurred in the clinical trials statistically significantly more frequently during treatment with mirtazapine than with placebo, added with adverse reactions from spontaneous reporting. The frequencies of the adverse reactions from spontaneous reporting are based on the reporting rate of these events in the clinical trials. The frequency of adverse reactions from spontaneous reporting for which no cases in the randomized placebo-controlled patient trials were observed with mirtazapine has been classified as 'not known'.
Table 1. Adverse reactions of mirtazapine


System organ class      Very common      Common          Uncommon           Rare            Frequency not known (≥1/10)          (≥1/100 to      (≥1/1,000 to       (≥1/10,000 to   (cannot be estimated <1/10)          <1/100)            <1/1,000)       from the available data)
Blood and the                                                                               Bone marrow lymphatic system                                                                            depression disorders                                                                                   (granulocytopenia, agranulocytosis,
aplastic anaemia
thrombocytopenia)
Eosinophilia
Endocrine disorders                                                                         Inappropriate antidiuretic hormone
secretion
Hyperprolactinemia
(and related
symptoms
galactorrhoea and
gynaecomastia)
Metabolism and          Weight                                                              Hyponatraemia nutrition disorders     increased1
Increase in
appetite1
Psychiatric disorders                    Abnormal        Nightmares2         Aggression     Suicidal ideation6 dreams          Mania                              Suicidal behaviour6 Confusion       Agitation2                         Somnambulism
Anxiety2, 5     Hallucinations
Insomnia3, 5    Psychomotor
restlessness (incl.
akathisia,
hyperkinesia)
Nervous system          Somnolence1, 4   Lethargy1       Paraesthesia2      Myoclonus       Convulsions (insults) disorders               Sedation1, 4     Dizziness       Restless legs                      Serotonin syndrome Headache2        Tremor          Syncope                            Oral paraesthesia Dysarthria
Vascular disorders                       Orthostatic     Hypotension2 hypotension
Gastrointestinal        Dry mouth        Nausea3         Oral               Pancreatitis    Mouth oedema disorders                                Diarrhoea2      hypoaesthesia                      Increased salivation Vomiting2
Constipation1
Hepatobiliary                                                               Elevations in disorders                                                                   serum transaminase
activities
Skin and                                 Exanthema2                                         Stevens- Johnson subcutaneous tissue                                                                         Syndrome disorders                                                                                   Dermatitis bullous Erythema multiforme
Toxic epidermal
necrolysis
Musculoskeletal and                      Arthralgia                                         Rhabdomyolysis connective tissue                        Myalgia
disorders                                Back pain1
Renal and urinary                                                                                 Urinary retention disorders
General disorders                        Oedema                                                   Generalised oedema and administration                       peripheral1                                              Localised oedema site conditions                          Fatigue
Investigations                                                                                    Increased creatinine kinase



1
In clinical trials these events occurred statistically significantly more frequently during treatment with mirtazapine than with placebo.
2
In clinical trials these events occurred more frequently during treatment with placebo than with mirtazapine, however not statistically significantly more frequently.
3
In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with mirtazapine.
4
N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.
5
Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under mirtazapine treatment, development or aggravation of anxiety and insomnia has been reported.
6
Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation (see section 4.4).

In laboratory evaluations in clinical trials transient increases in transaminases and gammaglutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with mirtazapine than with placebo).

Paediatric population

The following adverse events were observed commonly in clinical trials in children: weight gain, urticaria and hypertriglyceridaemia (see also section 5.1).

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