Excipients/Inactive Ingredients: F-Melt (Type C) (Mannitol, Microcrystalline cellulose, Crospovidone, Xylitol and Monobasic calcium phosphate), D-mannitol (SD-200), Crospovidone, Croscarmellose sodium, Potassium acesulfame, Sucralose, Xylitol, Aspartame, Orange micron, Magnesium stearate and Colloidal silicone dioxide.
Mirta Orodispersible Tablet is indicated in adults for the treatment of episodes of major depression.
Posology: Adults: The effective daily dose is usually between 15 and 45 mg; the starting dose is 15 or 30 mg.
Mirta Orodispersible Tablets 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.
It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms.
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). This should be taken into account when prescribing mirtazapine to this category of patients.
Hepatic impairment: The clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing Mirta Orodispersible Tablets to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated.
Paediatric population: Mirta Orodispersible Tablets should not be used in children and adolescents under the age of 18 years as efficacy was not demonstrated in two short-term clinical trials and because of safety concerns.
Method of administration: Mirta Orodispersible Tablets has an elimination half-life of 20-40 hours and therefore Mirta Orodispersible Tablets is suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Mirta Orodispersible Tablets 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. The tablet will rapidly disintegrate and can be swallowed without water.
Present experience concerning overdose with Mirta Orodispersible Tablets 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 receive appropriate symptomatic and supportive therapy for vital functions. Activated charcoal or gastric lavage should also be considered.
Paediatric population: The appropriate actions as described for adults should be taken in case of an overdose in paediatrics.
Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors.
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 behavior or thoughts and unusual changes in behavior 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 Mirtazapine orodispersible 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, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with Mirta Orodispersible Tablets. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with Mirta Orodispersible Tablets. In the post marketing period with Mirta Orodispersible Tablets 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 Mirta Orodispersible Tablets treatment, as with other antidepressants, Mirta Orodispersible Tablets 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 Mirta Orodispersible Tablets, 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 Mirta Orodispersible Tablets, 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 hypoglycemic 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. Mirta Orodispersible Tablets should be discontinued in any patient entering a manic phase.
Although Mirta Orodispersible Tablets 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. It is recommended to discontinue treatment with mirtazapine 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 (although there is little chance of problems with Mirta Orodispersible Tablets because of its very weak anticholinergic activity).
Akathisia/psychomotor restlessness: The use of antidepressants has been associated with the development of akathisia characterized by a subjectively unpleasant or distressing restlessness and 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.
Cases of QT prolongation, Torsade de Pointes, ventricular tachycardia, and sudden death, have been reported during the post marketing use of mirtazapine. 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. Caution should be exercised when Mirta Orodispersible Tablets 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 very rarely with the use of mirtazapine. 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 selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances. 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.
Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine. Treatment with Mirta Orodispersible Tablets should be discontinued if such events occur and supportive symptomatic treatment initiated. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with Mirta Orodispersible Tablets alone.
Aspartame: Mirta Orodispersible Tablets contains aspartame a source of phenylalanine. It may be harmful for patients with phenylketonuria.
QT Prolongation / Torsade de Pointes: Cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, ventricular fibrillation, cardiac arrest, and sudden death, have been reported during the post-marketing use of mirtazapine. 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. Caution should be exercised when mirtazapine 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. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death. Monitoring of vital signs and cardiac rhythm should be undertaken in the management of mirtazapine overdose.
Use with linezolid: Serotonergic psychiatric drugs should not be started in a patient receiving linezolid. Wait until 24 hours after the last dose of linezolid before starting the serotonergic psychiatric drugs.
Effects on ability to drive and use machines: Mirta Orodispersible Tablets has minor or moderate influence on the ability to drive and use machines. Mirta Orodispersible Tablets 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.
Use in Children: Mirta Orodispersible Tablets should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviour (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior 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 behavioral development are lacking.
Use in Elderly: Older people are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with Mirta Orodispersible Tablets, undesirable effects have not been reported more often in elderly patients than in other age groups.
Pregnancy: Limited data of the use of Mirta Orodispersible Tablets in pregnant women do not indicate an increased risk for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to Mirta Orodispersible Tablets treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).
Caution should be exercised when prescribing to pregnant women. If Mirta Orodispersible Tablets is used until, or shortly before birth, postnatal monitoring of the newborn is recommended to account for possible discontinuation effects.
Breast-feeding: Animal studies and limited human data have shown excretion of Mirta Orodispersible Tablets in breast milk only in very small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Mirta Orodispersible Tablets should be made taking into account the benefit of breastfeeding to the child and the benefit of Mirta Orodispersible Tablets therapy to the woman.
Fertility: Non-clinical reproductive toxicity studies in animals did not show any effect on fertility.
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 Mirta Orodispersible Tablets.
The most commonly reported adverse reactions, occurring in more than 5 % of patients treated with Mirta Orodispersible Tablets in randomized placebo-controlled trials (see as follows) 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 Mirta Orodispersible Tablets. 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. The table shows the categorized incidence of the adverse reactions, which occurred in the clinical trials statistically significantly more frequently during treatment with Mirta Orodispersible Tablets 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 Mirta Orodispersible Tablets has been classified as 'not known'. (See table.)
Click on icon to see table/diagram/image
In laboratory evaluations in clinical trials transient increases in transaminases and gamma glutamyl transferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with Mirta Orodispersible Tablets than with placebo).
The following adverse events were observed commonly in clinical trials in children: weight gain, urticaria and hypertriglyceridemia.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Pharmacodynamic interactions: Mirta Orodispersible Tablets should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy. In the opposite way about two weeks should pass before patients treated with mirtazapine should be treated with MAO inhibitors. In addition, as with SSRIs, co-administration with other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, methylene blue, SSRIs, venlafaxine, lithium and St. John's Wort - Hypericum perforatum - preparations) may lead to an incidence of serotonin associated effects. Caution should be advised and a closer clinical monitoring is required when these active substances are combined with Mirta Orodispersible Tablets.
Mirta Orodispersible Tablets may increase the sedating properties of benzodiazepines and other sedatives (notably most antipsychotics, antihistamine H1 antagonists, opioids). Caution should be exercised when these medicinal products are prescribed together with Mirta Orodispersible Tablets.
Mirta Orodispersible Tablets may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.
Mirta Orodispersible Tablets dosed at 30 mg once daily caused a small but statistically significant increase in the international normalized ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine a more pronounced effect cannot be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.
The risk of QT prolongation and/or ventricular arrhythmias (e.g. Torsade de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g. some antipsychotics and antibiotics).
Pharmacokinetic interactions: Carbamazepine and phenytoin, CYP3A4 inducers, increased Mirta Orodispersible Tablets clearance about twofold, resulting in a decrease in average plasma mirtazapine concentration of 60% and 45%, respectively. When carbamazepine or any other inducer of hepatic metabolism (such as rifampicin) is added to Mirta Orodispersible Tablets therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the Mirta Orodispersible Tablets dose.
Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40 % and 50 % respectively.
When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with Mirta Orodispersible Tablets, the mean plasma concentration of mirtazapine may be increased more than 50%. Caution should be exercised and the dose may have to be decreased when co-administering Mirta Orodispersible Tablets 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 Mirta Orodispersible Tablets with paroxetine, amitriptyline, risperidone or lithium.
Paediatric population: Interaction studies have only been performed in adults.
N06AX11 - mirtazapine ; Belongs to the class of other antidepressants.
Orodispersible tab 15 mg (white, round, with orange flavor engraved M15 on one side) x 3 x 10's. 30 mg (white, round, with orange flavor engraved M3 on one side) x 3 x 10's.