MIRTAZAPINE

Posology Adults The effective daily dose is usually between 15 mg (1 ml) and 45 mg (3 ml); the starting dose is 15 mg (1 ml) or 30 mg (2 ml). 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 elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response. 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). 1). 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 The solution is withdrawn from the bottle with the oral syringe and can be swallowed directly from the oral syringe.

Alternatively, it can be dosed onto a spoon or into a glass of water using the syringe. Instructions for use: • Open the bottle: press the cap and turn it anticlockwise (Figure 1). • Insert the syringe adaptor into the bottle neck (Figure 2).

• Take the syringe and put it in the adaptor opening (Figure 3). • Turn the bottle upside down (Figure 4). • Fill the syringe with a small amount of solution by pulling the piston down (Figure 4A). Then push the piston upward in order to remove any possible bubbles (Figure 4B).

Finally, pull the piston down to the graduation mark corresponding to the quantity in millilitres (ml) prescribed by your doctor. The top flat edge of the piston should be in line with the graduation mark you are measuring to (Figure 4C).

• Turn the bottle the right way up (Figure 5A). • Remove the syringe from the adaptor (Figure 5B). • Put the end of the syringe into your mouth and push the piston slowly back in to take the medicine. Alternatively, dispense the solution onto a spoon or into a small glass of water and take your medicine straight away.

• Wash the syringe with water and let it dry before you use it again (Figure 6). • Close the bottle with the plastic screw cap - leave the syringe adaptor in the bottle.

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.

Summary of safety profile 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.

4). Tabulated list of adverse reactions 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 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 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 (≥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 (granulocytopenia, agranulocytosis, aplastic anaemia, thrombocytopenia) Eosinophilia Endocrine disorders Inappropriate antidiuretic hormone secretion Hyperprolactinemi a (and related symptoms galactorrhea and gynecomastia) Metabolism and nutrition disorders Weight increased1 Increase in appetite1 Hyponatraemia Psychiatric disorders Abnormal dreams Confusion Anxiety2, 5 Insomnia3, 5 Nightmares2 Mania Agitation2 Hallucinations Psychomotor restlessness (incl.

akathisia, hyperkinesia) Aggression Suicidal ideation6 Suicidal behaviour6 Somnambulism Nervous system disorders Somnolence1, 4 Sedation1, 4 Headache2 Lethargy1 Dizziness Tremor Amnesia* Paraesthesia2 Restless legs Syncope Myoclonus Convulsions (insults) Serotonin syndrome Oral paresthaesia Dysarthria Vascular disorders Orthostatic hypotension Hypotension2 Gastrointestinal disorders Dry mouth Nausea3 Diarrhea2 Vomiting2 Constipation1 Oral hypoaesthesia Pancreatitis Mouth oedema Increased salivation Hepatobiliary disorders Elevations in serum transaminase activities Skin and subcutaneous tissue disorders Exanthema2 Stevens-Johnson Syndrome Dermatitis bullous Erythema multiforme Toxic epidermal necrolysis Drug reaction with eosinophilia and systemic symptoms (DRESS) 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 Musculoskeletal and connective tissue disorders Arthralgia Myalgia Back pain1 Rhabdomyolysis Reproductive system and breast disorders Priapism Renal and urinary disorders Urinary retention General disorders and administration site conditions Oedema peripheral1 Fatigue Generalised oedema Localised oedema Investigations Increased creatine 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.

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). *In 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.

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 quantity of Mirtazapine oral solution 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 realized that these symptoms may be related to the underlying disease.

2, it is recommended to discontinue treatment with mirtazapine gradually. • Care should […]

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