Active ingredient: Mirtazapine 30 mg.
Excipients/Inactive Ingredients: Lactose monohydrate, maize starch, hyroxypropyl cellulose - M, colloidal anhydrous silica, magnesium stearate, hypromellose 6 cps, macrogol 6000, titanium dioxide, red ferric oxide, yellow ferric oxide, caramel color.
Pharmacotherapeutic Group: Other antidepressants. ATC Code: N06AX11.
Pharmacology: Pharmacodynamics: Mirtazapine is an antidepressant which can be given as treatment for episodes of major depression. The presence of symptoms, e.g. anhedonia, psychomotor inhibition, sleep disturbances (early wakening) and weight loss, increase the chance of a positive response. Other symptoms are loss of interest, suicidal thoughts and changes in mood (better in the evening than in the morning). Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment.
Mirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission specifically mediated via 5-HT1 receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2 receptors and the R(-) enantiomer by blocking 5-HT3 receptors. The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. Mirtazapine is usually well tolerated. It has practically no anticholinergic activity and, at therapeutic doses, has practically no effect on the cardiovascular system.
Pharmacokinetics: After oral administration of mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability 50%), reaching peak plasma levels after approximately two hours.
Binding of mirtazapine to plasma proteins is approximately 85%. Mirtazapine is extensively metabolised in the liver by CYP2D6, CYP1A2, CYP3A4. Elimination is via urine (75%) and faeces (15%). The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and short half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range. Mirtazapine is extensively metabolized and eliminated via the urine and faeces within few days. Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound. The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.
Treatment of episodes of major depression.
Mirastad 30 are administrated orally.
Adults: The starting dose is 15 or 30 mg daily. The dosage generally needs to be increased to obtain an optimal clinical response. The effective daily dose is usually between 15 and 45 mg.
Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Usually need to increase the dose (at least after 1-2 weeks) to achieve optimal clinical response. 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.
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.
Children: 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.
Renal and hepatic insufficiency: The clearance of mirtazapine may be decreased in patients with moderate to severe renal (creatinine clearance <40 ml/min) or hepatic insufficiency. This should be taken into account when prescribing mirtazapine to this category of patients.
Mirtazapine has an elimination half-life of 20-40 hours and therefore mirtazapine are suitable for once-a-day administration 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).
Symptoms: Present experience concerning 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.
Treatment: Cases of overdose should receive appropriate symptomatic and supportuve therapy for vital functions. ECG monitoring should be undertaken. Activated charcoal or gastric lavage should also be considered.
Hypersensitivity to mirtazapine or to any ingredient in the formulation.
Concomitant use of mirtazapine with monoamine oxidase inhibitors.
Worsening of depression and/or emergence of suicidal ideation and behavior suicidality or unusal changes in the behavior may occur in both adult and pediatric patients with major depressive disorder and other psychiatric disorder, whether or not they are taking antidepressants. This risk may persist until clinical important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, these has been a long standing concern that antidepressants may have a role in including worsening of the depression and the emergence of the suicidality in the certain patients during the early phases of treatment.
Mirtazapine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviors (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 carfeully 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.
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 to symptoms such as fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, treatment should be stopped and blood counts taken.
Careful dosing as well as regular and close monitoring is necessary in patients with: Epilepsy and organic brain syndrome: From clinical experience it appears that insults occur rarely in patients treated with mirtazapine.
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.
As with other antidepresants, care should be taken in patients with: Micturition disturbances like prostate hypertrophy (although problems are not to be expected because mirtazapine possesses only very weak anticholinergic activity).
Acute narrow-angle glaucoma and increased intra-ocular pressure (also here little chance of problems with mirtazapine because of its very weak anticholinergic activity).
Treatment should be discontinued if jaundice occurs.
Moreover, as 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 manic-depressive psychosis is being treated, it can transfrom into the manic phase.
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.
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. It is recommended to discontinue treatment with mirtazapine gradually.
The use of antidepressants have been associated with the development of akathisia. 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. 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 Q Tc interval.
Hyponatraemia 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 may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances. Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.
Elderly patients are often more sensitive, especially with regard to the side-effects of antidepressants. During clinical research with mirtazapine, side-effects have not been reported more often in elderly patients than in other age groups; however experience until now is limited.
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.
Weight gain:Weight gain ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. In a 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients.
Cholesterol and triglycerides: In US controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine, compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglycerides to ≥500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline.
Transaminase elevations: Clinically significant alanine aminotransferase (ALT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% of patients exposed to mirtazapine in a pool of short-term US controlled trials, compared to 0.3% of placebo patients and 2.0% of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine should be used with caution in patients with impaired hepatic function.
Orthostatic hypotension: Mirtazapine was associated with significant orthostatic hypotension was infrequently observed in clinical trials with depressed patients.
Effects on ability to drive and use machines: Mirtazapine may impair concentration and alertness. Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery.
Pregnancy: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Lactation: Because some mirtazapine may be excreted into breast milk, caution should be exercised when mirtazapine are administered to nursing women.
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.
Very common (1/10 ≤ ADR):
Metabolism and nutrition: Weight increased, increase in appetite.
Nervous system: Somnolence, sedation, headache.
Gastrointestinal: Dry mouth.
Common (1/100 ≤ ADR <1/10):
Psychiatric: Abnormal dreams, confusion, anxiety, insomnia.
Nervous system: Lethargy, dizziness, tremor.
Vascular: Orthostatic hypotension.
Gastrointestinal: Nausea, diarrhea, vomiting, constipation.
Skin and subcutaneous tissue: Exanthema.
Musculo-skeletal and connective tissue: Arthralgia, myalgia, back pain.
General: Oedema peripheral, fatigue.
Uncommon (1/1000 ≤ ADR <1/100):
Psychiatric: Nightmares, mania, agitation, hallucinations, psychomotor restlessness (including akathisia, hyperkinesia).
Nervous system: Paraesthesia, restless legs, syncope.
Gastrointestinal: Oral hypoaesthesia.
Rare (1/10000 ≤ ADR <1/1000):
Nervous system: Myoclonus.
Hepatobiliary: Elevations in serum transaminase activities.
Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.
Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy.
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 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).
The enzyme inhibitor drug metabolism CYP3A4, CY2D6 and CYP1A2 (cimetidine, azole antifungal derivatives, viral HIV-protease inhibitor drugs, erythromycin) increase the concentration in the blood and may increase the toxicity of mirtazapine. Conversely, carbamazepine and other inducers of CYP3A4 increased the clearance of mirtazapine and the dose of mirtazapine may need to be increased when given with these drugs.
Incompatibilities: In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.
Store in a well-closed container, in a dry place, protect from light. Do not store above 30°C.
Shelf-Life: 24 months from the date of manufacturing.
N06AX11 - mirtazapine ; Belongs to the class of other antidepressants.
FC tab 30 mg (light brown, oval-shaped, film-coated tablet, biconvex, engraved with "STADA" on one side and scored on the other side) x 2 x 14's.