Mirzentac

Mirtazapine.

Per tablet: Mirtazapine 15 mg or 30 mg.
Excipients/Inactive Ingredients: Lactose hydrate, Corn starch, Hydroxypropylcellulose, Colloidal silicon dioxide, Magnesium stearate, Purified water.
15 mg: Opadry-Yellow (04F620003).
30 mg: Opadry-Orange (04F23084).

Mirzentac tablets are indicated in adults for the treatment of episodes of major depression.

Adult: 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.
It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms (see Contraindications and Precautions).
Elderly: 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 (see Contraindications and Precautions).
Hepatic impairment: The clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing mirtazapine to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated.
Paediatric population: Mirtazapine 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: 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.
The tablet is not sub-divisible. For doses not a multiple of 15 mg or 30 mg, consider using an appropriate strength of other brands in the market.

Present experience concerning overdose with mirtazapine 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. ECG monitoring should be undertaken. 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.

Mirzentac Tablets are contraindicated in patients with a known hypersensitivity to mirtazapine or to any of the excipients (see Description).
Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors (see Interactions).

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.
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 mirtazapine film-coated tablets should be given to the patient consistent with good patient management, in order to reduce the risk of overdose.
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.
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 (see as follows); hepatic impairment (see as follows); renal impairment (see as follows); 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 (see as follows).
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.
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. As advised in Dosage & Administration, 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 intraocular pressure (although there is little chance of problems with mirtazapine because of its very weak anticholinergic activity).
The use of antidepressants have been associated with the development of akathisia, characterised 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, 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.
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 mirtazapine 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 mirtazapine alone.
Excipients: Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.
Use in Children: 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 behavioural development are lacking.
Use in the Elderly: Elderly patients are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with mirtazapine, undesirable effects have not been reported more often in elderly patients than in other age groups.

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 randomized placebo-controlled trials 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 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.
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 have been reported in association with mirtazapine treatment.
The table 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'. (See table.)

Click on icon to see table/diagram/image

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).
Paediatric population: The following adverse events were observed commonly in clinical trials in children: weight gain, urticaria and hypertriglyceridaemia.

Pharmacodynamic interactions: Mirtazapine 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, methylene blue, SSRIs, venlafaxine, lithium and St. John's Wort - Hypericum perforatum - preparations) may lead to an incidence of serotonin-associated effects (serotonin syndrome). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.
Mirtazapine 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 mirtazapine.
Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.
Mirtazapine 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 mirtazapine clearance about two-fold, 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 mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the mirtazapine 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 mirtazapine, the mean plasma concentration of mirtazapine may increase more than 50%. Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine 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 mirtazapine with paroxetine, amitriptyline, risperidone or lithium.
Paediatric population: Interaction studies have only been performed in adults.

Shelf-life: 24 months from the manufacturing date.

Antidepressants

N06AX11 - mirtazapine ; Belongs to the class of other antidepressants.

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