Remeron 15 mg,30 mg Tablet

Treatment of episodes of major depression.

The tablets should be taken orally, if necessary with fluid, and swallowed without chewing.

Initial treatment

Adults

The recommended starting dose for REMERON (mirtazapine) is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In clinical trials the effective dose range was generally 15 to 45 mg/day. REMERON has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than 1 to 2 weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. With an insufficient response, the dose can be increased up to the maximum dose of 45 mg per day. If there is no response within a further 2 to 4 weeks, the treatment should be stopped.

Elderly

The recommended dose is the same as that for adults. However, in elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response. The clearance of REMERON is reduced in elderly patients. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patients, compared to levels observed in younger adults (see PHARMACOLOGICAL ACTION, Pharmacokinetic properties).

Children and adolescents under the age of 18 years

REMERON should not be used in children and adolescents under the age of 18 years (see WARNINGS AND SPECIAL PRECAUTIONS).

Renal impairment

The clearance of REMERON may be decreased in patients with moderate to severe renal impairment (creatinine clearance < 40 mL/min). This should be taken into account when prescribing REMERON to this category of patients (see WARNINGS AND SPECIAL PRECAUTIONS).

Hepatic impairment

The clearance of REMERON may be decreased in patients with hepatic impairment. This should be taken into account when prescribing REMERON to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see PHARMACOLOGICAL ACTION, Pharmacokinetic properties and WARNINGS AND SPECIAL PRECAUTIONS). REMERON has an elimination half-life of 20 to 40 hours and therefore REMERON is suitable for once-a-day administration. It should be taken preferably as a single night-time dose before going to bed. REMERON 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). Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms. It is recommended to discontinue treatment with REMERON gradually to avoid withdrawal symptoms (see WARNINGS AND SPECIAL PRECAUTIONS).

• Hypersensitivity to the active substance or to any of the excipients.
• Children and adolescents under the age of 18 years (see WARNINGS AND SPECIAL PRECAUTIONS).
• Concomitant monoamine oxidase inhibitors or within 14 days of discontinuation thereof (see INTERACTIONS).

Use in children and adolescents under 18 years of age

REMERON 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.

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 number of REMERON film-coated tablets should be given to the patient.

Bone marrow depression

Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with REMERON. In the post-marketing period with REMERON cases of agranulocytosis has also been reported, mostly reversible, but in some cases fatal. Fatal cases mostly concerned patients with an age above 65. One should therefore be alert for symptoms like fever, sore throat, stomatitis or other signs of infections. If such symptoms occur the 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 symptoms: REMERON 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 REMERON, the clearance of REMERON was approximately 35 % decreased in mild to moderate hepatically impaired patients, compared to subjects with normal hepatic function. The average plasma concentration of REMERON was about 55 % increased.
• Renal impairment: Following a single 15 mg oral dose of REMERON, in patients with moderate (10 mL/min u2264 creatinine clearance < 40 mL/min) and severe (creatinine clearance < 10 mL/min) renal impairment, the clearance of REMERON was about 30 % and 50 % decreased respectively, compared to normal subjects. The average plasma concentration of REMERON was about 55 % and 115 % increased respectively. No significant differences were found in patients with mild renal impairment (40 mL/min u2264 creatinine clearance < 80 mL/min) as compared to the control group.
• Cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarct, where normal precautions should be taken and concomitant medicines carefully administered.
• Low blood pressure.
• Diabetes mellitus: In patients with diabetes, antidepressants such as REMERON may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted, and close monitoring is recommended.

The following should be taken into account:

• Worsening psychotic symptoms can occur when REMERON is 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.
• Post-marketing experience shows that abrupt termination of treatment after long term administration of REMERON may 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 were the most frequently reported. As advised in DOSAGE AND DIRECTIONS FOR USE, it is recommended to discontinue treatment with REMERON gradually.
• Care should be taken in patients with micturition disturbances like prostate hypertrophy and in patients with acute narrow-angle glaucoma and increased intra-ocular pressure.
• Akathisia/psychomotor restlessness: The use of REMERON has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and a need to move often, accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

The effect of REMERON (mirtazapine) on QTc interval was assessed in a randomised, placebo and moxifloxacin controlled clinical trial involving 54 healthy volunteers using exposure response analysis. This trial revealed that both 45 mg (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine did not affect the QTc interval to a clinically meaningful extent. During the post-marketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia and sudden death, have been reported. The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc prolonging medicines (see INTERACTIONS and KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT). Caution should be exercised when REMERON is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QTc interval.

Hyponatraemia: Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported with the use of REMERON. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatraemia.

Serotonin syndrome: Interaction with serotonergic active substances: Serotonin syndrome may occur when REMERON is used concomitantly with other serotonergic active substances (see INTERACTIONS). Symptoms of serotonin syndrome may be hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Interaction with other medicaments and other forms of interaction:

Pharmacodynamic interactions

• REMERON may potentiate the central nervous dampening action of alcohol; patients should therefore be advised to avoid alcohol during treatment with REMERON.
• REMERON should not be administered concomitantly with MAO Inhibitors, including linezolid, or within 2 weeks of cessation of therapy with these agents, (see CONTRAINDICATIONS).
• In the opposite way, about 2 weeks should pass before patients treated with REMERON should be treated with MAO inhibitors (see CONTRAINDICATIONS).
• Co-administration with other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, methylene blue, SSRIs, venlafaxine, lithium and St. Johnu2019s Wort - Hypericum perforatum - preparations) may lead to an incidence of serotonin-associated effects (serotonin syndrome: see WARNINGS AND SPECIAL PRECAUTIONS). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with REMERON.
• REMERON may potentiate the sedative effects of benzodiazepines and other sedatives (including antipsychotics, antihistamine H1 antagonists, opioids). Caution should be taken when these medicinal products are prescribed together with REMERON.
• REMERON dosed at 30 mg once daily caused a small, but statistically significant increase in the international normalised ratio (INR) in subjects treated with warfarin. As at a higher dose of REMERON a more pronounced effect cannot be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with REMERON.
• The risk of QT prolongation and/or ventricular dysrhythmias (e.g. Torsades de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g. some antipsychotics and antibiotics) and in case of mirtazapine overdose.
• REMERON may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking REMERON.

Pharmacokinetic interactions

• Carbamazepine and phenytoin, and CYP3A4 inducers, increased REMERON clearance about two-fold, resulting in a decrease in average plasma REMERON concentration of 60 % and 45 %, respectively. When carbamazepine or any other inducer of hepatic metabolism (such as rifampicin) is added to REMERON therapy, the REMERON dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the REMERON dose.
• Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of REMERON by approximately 40 % and 50 %, respectively.
• When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with REMERON, the mean plasma concentration of REMERON may increase more than 50 %. Caution should be exercised and the dose may have to be decreased when co-administering REMERON with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine or nefazodone.
• Interaction studies did not indicate any relevant pharmacokinetic effects on concurrent treatment of REMERON with paroxetine, amitriptyline, risperidone or lithium.

Safety in pregnancy and lactation has not been demonstrated. Women on REMERON should not breastfeed.

REMERON may impair concentration and alertness (particularly in the initial phase of treatment). Patients should avoid the performance of potentially dangerous tasks which require alertness and good concentration, such as driving a motor vehicle or operating machinery, at any time when affected.

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

All randomised placebo-controlled trials in patients (including indications other than major depressive disorder), have been evaluated for adverse reactions of REMERON. 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 REMERON 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 significantly more frequently during treatment with REMERON 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.

Table 1. Adverse reactions of REMERON

System organ class

Very common ( u2265 1/10)

Common ( u2265 1/100 to < 1/10)

Uncommon ( u2265 1/1 000 to < 1/100)

Rare ( u2265 1/10 000 to < 1/1 000)

Metabolism and nutrition disorders

Weight increased 1

Increase in appetite 1

Psychiatric disorders

Abnormal dreams

Confusion

Nightmares 2

Mania

Agitation 2

Aggression

Anxiety 2, 5

Insomnia 3, 5

Hallucinations

Psychomotor restlessness (incl. akathisia, hyperkinesia)

Nervous system disorders

Somnolence 1, 4

Sedation 1, 4

Headache 2

Lethargy 1

Dizziness

Tremor

Paraesthesia 2

Restless legs

Syncope

Myoclonus

Vascular disorders

Orthostatic hypotension

Hypotension 2

Gastrointestinal disorders

Dry mouth

Nausea 3

Diarrhoea 2

Vomiting 2

Constipation 1

Oral hypoaesthesia

Pancreatitis

Hepatobiliary disorders

Elevations in serum transaminase activities

Skin and subcutaneous tissue disorders

Exanthema 2

Musculoskeletal, connective tissue and bone disorders

Arthralgia

Myalgia

Back pain 1

General disorders and administration site conditions

Oedema peripheral 1

Fatigue

In clinical trials these events occurred statistically significantly more frequently during treatment with REMERON than with placebo.

In clinical trials these events occurred more frequently during treatment with placebo than with REMERON, however not statistically significantly more frequently.

In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with REMERON.

N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardise antidepressant efficacy.

Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under REMERON treatment, development or aggravation of anxiety and insomnia has been reported. 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 REMERON than with placebo). The frequency of adverse reactions from spontaneous reporting for which no cases in the randomised placebo-controlled patient trials were observed with REMERON has been classified as u2018not knownu2019.

Post-marketing side effects

The reported post-marketing adverse reactions of which the frequency is not known are:

Blood and the lymphatic system disorders: bone marrow depression (granulocytopenia, agranulocytosis, aplastic anaemia and thrombocytopenia), eosinophilia

Metabolism and nutrition disorders: hyponatraemia

Psychiatric disorders: suicidal ideation 6, suicidal behaviour 6, somnambulism

Nervous system disorders: convulsions (insults), serotonin syndrome, oral paraesthesia, dysarthria

Gastrointestinal disorders: mouth oedema, increased salivation

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, dermatitis bullous, erythema multiforme, toxic epidermal necrolysis

General disorders and administration site conditions: generalised oedema, localised oedema.

Renal and urinary disorders: urinary retention

Investigations: increased creatine kinase

Musculoskeletal and connective tissue disorders: rhabdomyolysis 7

Endocrine disorders: hyperprolactinemia (and related symptoms e.g. galactorrhoea and gynecomastia)

6 Cases of suicidal ideation and suicidal behaviours, including attempted suicide, have been reported during REMERON therapy or early after treatment discontinuation (see WARNINGS AND SPECIAL PRECAUTIONS).

7 Cases of rhabdomyolysis have been reported in association with serotonin syndrome and multi-drug overdose. In the latter, a causative association with mirtazapine cannot be ascertained.

Present experience concerning overdose with REMERON alone indicates that symptoms are usually mild. Depression of the central nervous system with disorientation and prolonged sedation have been reported, together with tachycardia and mild hyper- or hypotension. However, there is a possibility of more serious outcomes (including fatalities) at dosages much higher than the therapeutic dose, especially with mixed overdoses. In these cases QT-prolongation and Torsade de Pointes have also been reported.

Cases of overdose should be treated by gastric lavage with appropriate symptomatic and supportive therapy for vital functions. ECG monitoring should be undertaken.