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). Elderly The recommended dose is same as that for adults. In elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response. 1).

Renal impairment:

The clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40 ml/min). 4).

Hepatic impairment:

The clearance of mirtazapine may be decreased in patients with hepatic impairment. 4). Method of administration The tablets should be swallowed whole without chewing, with a sufficient amount of fluid. The tablets should be taken orally.

Mirtazapine tablets can be taken once daily, since the elimination half-life is 20 to 40 hours. The medicine should be taken preferably as a single dose immediately before bedtime. The daily dose can also be divided into two doses taken in the morning and at the night-time.

The higher dose should be taken at night.

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 mirtazapine treatment.

4) 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.

Tabulated list of adverse reactions 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 60mg 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 for 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 reaction’s to Mirtazapine System organ class 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) Frequency not known Blood and the lymphatic system disorders Bone marrow depression (granulocytopaenia, agranulocytosis, aplastic anaemia, thrombocytopaenia) Eosinophilia Endocrine disorders Inappropriate antidiuretic hormone secretion Hyperprolactinemia (and related symptoms galactorrhea and gynecomastia) Metabolism and nutrition disorders Weight increased 1 Increase in appetite 1 Hyponatraemia Psychiatric disorders Abnormal dreams Confusion Anxiety 2, 5 Insomnia 3, 5 Nightmares 2 Mania Agitation 2 Hallucinations Psychomotor restlessness (including akathisia, hyperkinesias) Aggression Suicidal ideation 6 Suicidal behaviour 6 Somnambulism Nervous system disorders Somnolence 1, 4 Sedation 1, 4 Headache 2 Lethargy 1 Dizziness Tremor Amnesia7 Paraesthesia2 Restless legs Syncope Myoclonus Convulsions (insults) Serotonin syndrome Oral paraesthesia Dysarthia System organ class 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) Frequency not known Vascular disorders Orthostatic hypotensio n Hypotension 2 Gastrointesti nal disorders Dry mouth Nausea 3 Diarrhoea 2 Vomiting 2 Constipatio n1 Oral hypoaesthesia Pancreatitis Mouth oedema Increased salivation Hepatobiliar y disorders Elevations in serum transaminase 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) Musculoskele tal & connective tissue disorders Arthralgia Myalgia Back pain 1 Rhabdomyolysis Renal and urinary disorders Urinary retention Reproductive system and breast disorders Priapism General disorders & administratio n site conditions Oedema peripheral 1 Fatigue Generalised oedema Localised oedema Investigation s Increased creatine kinase 1 In clinical trials these events occurred statistically significantly more frequently during treatment with Mirtazapine that 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.

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. 4) 7In most cases patients recovered after drug withdrawal. In laboratory evaluations in clinical trials transient increases in transaminases and gamma-glutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with Mirtazapine than with placebo).

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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4 Special warnings and special precautions for use Severe cutaneous adverse reactions Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), bullous dermatitis and erythema multiforme, which can be life- threatening or fatal, have been reported in association with mirtazapine treatment.

If signs and symptoms suggestive of these reactions appear, mirtazapine should be withdrawn immediately. If the patient has developed one of these reactions with the use of mirtazapine, treatment with mirtazapine must not be restarted in this patient at any time.

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 antidepressant drugs 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 drug 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 the smallest amount of Mirtazapine Tablets 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, which is usually manifested by granulocytopenia or agranulocytosis, has been reported in the users of mirtazapine. Reversible agranulocytosis has also been reported as a rare occurrence in clinical trials 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 attendant doctor should be alert for fever, throat pain, stomatitis and other signs and symptoms suggestive of infection.

If these manifestations occur, the treatment should be discontinued and a complete blood count should be taken. Jaundice The treatment should be discontinued in the presence of jaundice. Conditions which need supervision Careful dosing as well as regular and close monitoring is necessary in patient with: • Epilepsy or organic brain syndrome: Although clinical experience indicates that epileptic seizures are rare during mirtazapine treatment and 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, such as conduction disturbances, angina pectoris or recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered. • Low blood pressure • Diabetes mellitus: antidepressants may alter glycaemic control.

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

• When the depressive phase of a bipolar disorder is being treated, a switch to a manic phase may occur. 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 patients with […]

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