MIRTAZAPINE

Posology Adults The effective daily dose is usually between 15 and 45 mg; the starting dose is 15 or 30 mg. Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks.

With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped. Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

4). Older people The recommended dose is the same as that for adults. In older people, an increase in dosing should be done under close supervision to elicit a satisfactory and safe response. 1) Patients with renal impairment The clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40 ml/min).

4). Patients with hepatic impairment The clearance of mirtazapine may be decreased in patients with hepatic impairment. 4) Method of administration Mirtazapine has an elimination half-life of 20-40 hours and therefore mirtazapine is suitable for once daily administration.

It should be taken preferably as a single night-time dose before going to bed. Mirtazapine may also be given in two divided doses (once in the morning and once at night time, the higher dose should be taken at night). The tablets should be taken orally, with fluid, and swallowed without chewing.

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 randomised placebo-controlled trials (see below) are somnolence, sedation, dry mouth, weight increased, increase in appetite, dizziness and fatigue.

4). All randomised 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 1501 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 categorised incidence of the adverse reactions, which occurred in the clinical trials statistically more 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 randomised 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 (≥ 1/10) Common (≥ 1/100 to < 1/10) Uncommon (≥1/1,000 to < 1/100) Rare (> 1/10,00 0 to < 1/1,000) Not known (cannot be estimated from the available data) Blood and lymphatic disorders • Bone marrow depression (granulocytopeni a, agranulocytosis, aplastic anaemia and thrombocytopeni a) • Eosinophilia Endocrine disorders • Inappropriate antidiuretic hormone secretion • Hyperprolactine mia (and related symptoms galactorrhea and gynecomastia) Metabolism and nutrition disorders • Weight increase d1 • Increase • Hyponatraemia in appetite 1 Psychiatric disorders • Abnormal dreams • Confusion • Anxiety 2,5 • Insomnia 3,5 •Nightmares 2 •Mania •Agitation 2 •Hallucination s • Psychomotor restlessness (incl, akathisia, hyperkinesia) • Aggressi on • Suicidal ideation 6 • Suicidal behaviour 6 Nervous system disorders • Somnolence 1,4 • Sedation 1,4 • Headache 2 • Lethargy 1 • Dizziness • Tremor • Amnesia7 • Paraesthesia 2 • Restless legs • Syncope • Myoclon us • Convulsions (insults) • Serotonin syndrome • Oral paraesthesia • Dysarthria Vascular disorders • Orthostatic hypotension • Hypotension 2 Gastrointestin al disorders • Dry mouth • Nausea 3 • Diarrhoea 2 • Vomiting 2 • Constipation 1 • Oral hypoaesthesi a • Pancreatit is • Mouth oedema • Increased salivation Hepatobiliary disorders • Elevation s in serum transamin ase activities Skin and subcutaneous tissue disorders • Exanthema 2 • Stevens-Johnson syndrome • Dermatitis bullous • Erythema multiforme • Toxic epidermal necrolysis • Drug reaction with eosinophilia and systemic symptoms (DRESS) Musculoskelet al and connective tissue disorders • Arthralgia • Myalgia • Back pain 1 • Rhabdomyolysis Renal and urinary disorders • Urinary retention Reproductive system and breast disorders • Priapism General disorders and administration site conditions • Oedema peripheral 1 • Fatigue • Somnambulism • Generalised oedema • Localised oedema 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. B. dose reduction generally does not lead to less somnolence/sedation but can jeopardise antidepressant efficacy.

Paediatric population Mirtazapine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo.

If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Suicide/suicidal thoughts or clinical worsening Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.

It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

A meta-analysis of placebo- controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany therapy with antidepressants especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

With regard to the chance of suicide, in particular at the beginning of treatment, only a limited amount of mirtazapine should be given to the patient consistent with good patient management, in order to reduce the risk of overdose.

Bone marrow depression Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with mirtazapine. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with mirtazapine.

In the post-marketing period with mirtazapine, very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. Fatal cases mostly concerned patients with an age above 65. The physician should be alert for symptoms like fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, treatment should be stopped and blood counts taken.

Jaundice Treatment should be discontinued if jaundice occurs. Conditions which need supervision Careful dosing as well as regular and close monitoring is necessary in patients with: - epilepsy and organic brain syndrome: Although clinical experience indicates that epileptic seizures are rare during mirtazapine treatment, as with other antidepressants, mirtazapine should be introduced cautiously in patients who have a history of seizures.

Treatment should be discontinued in any patient who develops seizures, or where there is an increase in seizure frequency. - hepatic impairment: Following a single 15 mg oral dose of mirtazapine, the clearance of mirtazapine was approximately 35% decreased in mild to moderate hepatically impaired patients, compared to subjects with normal hepatic function.

The average plasma concentration of mirtazapine was about 55% increased. - renal impairment: Following a single 15 mg oral dose of mirtazapine, in patients with moderate (creatinine clearance < 40 ml/min) and severe (creatinine clearance ≤ 10 ml/min) renal impairment the clearance of mirtazapine was about 30 % and 50 % decreased respectively, compared to normal subjects.

The average plasma concentration of mirtazapine was about 55 % and 115 % increased respectively. No significant differences were found in patients with mild renal impairment (creatinine clearance < 80 ml/min) as compared to the control group.

- cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered. - low blood pressure. - diabetes mellitus: In patients with diabetes, antidepressants may alter glycaemic control.

Insulin and/or oral hypoglycaemic dosage may need to be adjusted and close monitoring is recommended. Like with other antidepressants, the following should be taken into account: - worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified.

- when the depressive phase of bipolar disorder is being treated, it can transform into the manic phase. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase.

- although mirtazapine is not addictive, post-marketing experience shows that abrupt termination of treatment after long term administration may sometimes result in withdrawal symptoms. The majority of withdrawal reactions are mild and self-limiting.

Among the various reported withdrawal symptoms, dizziness, agitation, anxiety, headache and nausea are the most frequently reported. Even though they have been reported as withdrawal symptoms, it should be realised that these symptoms may be related to the underlying disease.

2, it is recommended to discontinue treatment with mirtazapine gradually. - Care should be taken in […]

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