Mirtazonal

General characteristics. Structure:

Active agent: миртазапин 15 mg, 30 mg, 45 mg;
Excipients: Mannitolum of DC (Perlitol 200), cellulose microcrystallic (Avitsel PH 102), magnesium a carbonate, a gipromelloz with low extent of substitution (L-HPC, LH-11), кросповидон (Poliplasdon XL-10), cellulose microcrystallic + gum guar (Avitsel SE-15), silicon dioxide colloid (Aerosil 200), L-methionine, aspartame, fragrance orange Silesia 1209603133, magnesium stearate.

Description
Round biconvex tablets of white or almost white color with an orange smell with Ml engraving (a tablet of 15 mg), Sq.m (a tablet of 30 mg) or M4 (a tablet of 45 mg) on the one hand.

Pharmacological properties:

Mirtazapin is antidepressant of four-cycling structure with preferential sedative action. Drug is most effective at depressions with existence in a clinical picture of such symptoms as inability to feel pleasure and joy, interest loss (angedoniya), psychomotor block, sleep disorders (especially in the form of early awakenings) and loss of weight, and also other symptoms: suicide thoughts and daily mood swings.
The antidepressive effect of drug usually occurs in 1-2 weeks of treatment.

Pharmacodynamics. Mirtazapin is an antagonist of presynaptic ɑ2 adrenoceptors in the central nervous system and strengthens the central noradrenergichesky and serotonergic transfer of nervous impulses. At the same time strengthening of serotonergic transfer is implemented only through 5-HT1-retseptory as миртазапин blocks 5-HT2 and 5-HT3-retseptory. It is considered that both enantiomer of a mirtazapin have antidepressive activity (+) an enantiomer - blocking S ɑ2 and 5-HT2-retseptory, a R (-) an enantiomer - blocking 5-HT3 receptors.
Sedative properties of a mirtazapin are caused by its antagonistic activity in relation to H1-histamine receptors.
Mirtazapin is usually well had. In therapeutic doses has practically no anticholinergic effect and practically does not influence cardiovascular system.

Pharmacokinetics. After oral administration of drug миртазапин it is quickly soaked up (bioavailability about 50%), reaching the maximum concentration in a blood plasma approximately in 2 h. About 85% of a mirtazapin contact proteins of plasma. The average elimination half-life makes from 20 to 40 h (seldom to 65 h). Shorter elimination half-life is observed at young people. Stable concentration of substance is reached in 3-4 days and further it does not change. In the recommended range of doses pharmacokinetic indicators of a mirtazapin have linear dependence on the entered drug dose. Meal does not exert impact on drug pharmacokinetics, Mirtazapin is actively metabolized and brought by kidneys and through intestines within several days. The main ways of his metabolism in an organism are demethylation and oxidation with the subsequent conjugation. R450-cytochrome dependent isoenzymes of CYP2D6 and CYP1A2 participate in education 8-gidroksi-a metabolite of a mirtazapin while CYP3A4 isoenzyme presumably defines formation of N-demetilirovannykh and the N-oxidized metabolites. Demetil-mirtazapin pharmacological is active and, apparently, pharmacokinetically is similar to initial connection.
The clearance of a mirtazapin decreases at a renal or liver failure.

Indications to use:

Depressions (including angedoniya, psychomotor block, sleeplessness, early awakening, decrease in body weight, loss of interest in life, suicide thoughts and lability of mood).

Route of administration and doses:

The tablet for a rassasyvaniye should be put on language and to rassasyvat before its full disintegration.
Tablets for a rassasyvaniye Mirtazonal quickly collapse in language, their reception does not require liquid. And during its rassasyvaniye it is not necessary to try to destroy a tablet to administration of drug (to chew, break, etc.).
Adults: 
The recommended initial daily dose makes 15 or 30 mg/days which is gradually increased if necessary to 45 mg/days. The dose of drug should be accepted for the night once a day.
Elderly: 
The same recommended dose, as for adults. At elderly patients to achieve the satisfactory and safe response to treatment, increase in a dose it is necessary to make under direct observation of the doctor.
Children and teenagers up to 18 years: 
Safety and efficiency of drug Mirtazonal at treatment at children and teenagers aged up to 18 years with big depressive frustration in placebo - controlled tests were not established. Safety and efficiency in this population cannot be extrapolated on the basis of the data obtained at adults. Therefore, drug Mirtazonal should not be used at children and teenagers aged up to 18 years.
At patients with a renal or liver failure the clearance of a mirtazapin can be reduced. It should be considered at purpose of drug of this category of patients. The period a floor at removal of a mirtazapin makes 20-40 hours and therefore drug is suitable for reception once a day. It is more preferable to accept drug as a single dose before a night dream, Mirtazonal it is also possible to appoint Drug for reception two times a day, having divided a daily dose in half (once in the morning and once for the night). Treatment should be continued whenever possible to total absence of symptoms at the patient within 4-6 months. After that, treatment can be cancelled gradually. Mirtazapin begins to have the effect usually after 1-2 weeks of treatment. Treatment by an adequate dose has to lead to affirmative answer in 2-4 weeks. At the insufficient response to treatment the dose can be increased to the maximum dose. In case of lack of the response to treatment in 2-4 weeks treatment should be stopped.

Features of use:

At combined use with other drugs it must be kept in mind: Deterioration in psychotic symptoms can happen at use of antidepressants for treatment of patients to schizophrenia or other psychotic disturbances; the paranoid ideas can amplify.
At treatment of a depressive phase of bipolar affective psychosis inversion of affect with development of a mania can be observed.
The depression can be followed by the increased frequency of emergence of suicide thoughts and attempts of a suicide. This risk remains until emergence of remission of a disease. As improvement of a state can not occur in the first weeks of treatment, for the patient it is necessary to establish careful control before improvement of its state. Clinical experience shows that the risk of attempts of a suicide can increase at early stages of recovery. At patients with cases of suicide attempts is in the history of a disease or patients at whom the raised extent of emergence of suicide thoughts prior to treatment is observed there is an increased risk of emergence of attempts of a suicide, for such patients careful control is necessary. Placebo meta-analysis - controlled clinical trials of drugs of group of antidepressants at adult patients with mental deviations showed the increased risk of emergence of cases of a suicide at reception of antidepressants in comparison with placebo at a group of persons 25 years are younger.
Observation of patients, in particular behind those which concern to risk group, in particular at an early stage of therapy and during change of a dose of drug is necessary. Patients (and the people who are carrying out care of patients) have to be warned about need of observation of clinical signs of deterioration in a mental state, behind emergence of suicide attempts or thoughts and behind emergence of unusual changes in behavior. At emergence of these symptoms it is necessary to consult immediately with the attending physician.
Taking into account risk of a suicide, the patient should give only limited quantity of tablets.
The sharp termination of treatment after long use can become the reason of nausea, headache, an indisposition, alarm and concern.
Patients of advanced age are usually more sensitive, especially concerning side effects. In clinical trials of drug Mirtazonal it was not noted that at patients of advanced age side effects happen more often than in other age groups, but they can be more expressed; however data are still limited.
At emergence of symptoms of jaundice treatment should be interrupted.

• The patient recommend to avoid use of alcohol at treatment by drug.
• It is necessary to be careful, appointing benzodiazepines along with drug.
• The oppression of functions of marrow which is usually shown in the form of a granulocytopenia or an agranulocytosis is seldom observed at Mirtazonal's use. Appears mostly after 4-6 weeks of treatment and it is reversible after the treatment termination. The doctor should show consideration (and to inform the patient) for such symptoms as fervescence, pharyngalgias, stomatitis, and other signs of a grippopodobny syndrome; at emergence of similar symptoms it is necessary to stop treatment and to make blood test.
• Proceeding from post-registration experience, it turned out that the serotoninovy syndrome arises very seldom at the patients receiving treatment only drug Mirtazonal, Interaction with other serotonergic medicines (see the section "Interaction with Other Medicines"),
• Women of reproductive age should appoint treatment only on condition of use of reliable contraception.
Influence on ability to drive the car and to work with mechanisms
Mirtazonal can reduce concentration of attention. In the course of treatment by antidepressants patients should avoid performance of potentially dangerous types of activity demanding the high speed of psychomotor reactions, such as driving of the car or control of mechanisms.

Side effects:

At patients with a depression a number of the symptoms caused by a disease therefore it is sometimes difficult to distinguish the symptoms connected with a disease and the symptoms caused by drug use is observed.
The following side effects with a frequency can be observed: often (> 1/100); sometimes (> 1/1000, but <1/100); seldom (> 1/10000, but <1/1000); very seldom (<1/10000), including separate cases.
From a nervous system: 
often - drowsiness (which can lead to disturbance of concentration of attention), meets in the first weeks of treatment more often (N.B.: the dose decline usually does not lead to reduction of sedative action, but can have an adverse effect on efficiency of antidepressant); dizziness and headache.
Seldom - agitation, confusion of consciousness, sleeplessness, psychomotor excitement (including an akathisia, a hyperkinesia), alarm, a myoclonus, a hypokinesia, apathy, a hyperesthesia, a tremor, a convulsive syndrome, a syndrome of "uneasy legs", paresthesia, feeling of fatigue, a mania, hallucinations, night nightmares / bright dreams. Very seldom serotoninovy syndrome, paresthesia of a mucous membrane of an oral cavity. Frequency is not known - suicide thoughts and risk of a suicide;
From bodies of a hemopoiesis: 
seldom - hemopoiesis oppression (a granulocytopenia, a neutropenia, an agranulocytosis, aplastic anemia and thrombocytopenia), an eosinophilia.
From the alimentary system: 
sometimes - nausea; seldom - diarrhea, dryness in a mouth, increase in activity of transaminases in a blood plasma, vomiting, a lock, an abdominal pain; very seldom hypostasis of a mucous membrane of an oral cavity.
From urinogenital system: 
dysmenorrhea, dysuria.
From cardiovascular system: 
seldom - orthostatic hypotension, a lowering of arterial pressure.
From integuments: 
seldom - a dieback.
From a musculoskeletal system: 
seldom arthralgia, mialgiya,
Others: 
often - increase in appetite and increase in body weight, an edematous syndrome; seldom - a small tortoiseshell, a dorsodynia, a syndrome of "cancellation", thirst.

Interaction with other medicines:

Pharmakokshetichesky interaction

• Mirtazapin is intensively metabolized with participation of isoenzymes of CYP2D6 and CYP3A4, and to a lesser extent with participation of an isoenzyme of CYP1A2. Studying of interaction at healthy volunteers showed that пароксетин, CYP2D6 isoenzyme inhibitor, does not exert impact on pharmacokinetics of a mirtazapin at an equilibrium state. Introduction in combination with powerful inhibitor of an isoenzyme CYP3A4, ketokonazoly increased the maximum levels of concentration in plasma and the area under a curve "concentration time" of a mirtazapin approximately for 40% and 50%, respectively. It is necessary to show care at use of a mirtazapin in combination with powerful inhibitors of an isoenzyme CYP3A4, HIV protease inhibitors, azolny antifungal medicines, erythromycin or nefazodony,
• Carbamazepine and Phenytoinum, CYP3A4 isoenzyme inductors, increased clearance of a mirtazapin approximately twice that led to 45-60% to decrease in concentration of a mirtazapin in plasma. At addition of carbamazepine or other inductor of hepatic metabolism (for example, rifampicin) to therapy mirtazapiny the dose of a mirtazapin perhaps should be increased. At the treatment termination need of a dose decline of a mirtazapin can arise such medicine.
• At use in combination with Cimetidinum bioavailability of a mirtazapin can increase more than by 50%. The dose of a mirtazapin perhaps should be reduced at an initiation of treatment in combination with Cimetidinum or to increase at the treatment termination by Cimetidinum.
• In in vivo researches of interactions миртазапин did not exert impact on pharmacokinetics of a risperidon or a paroksetin (CYP2D6 isoenzyme substrate), carbamazepine and Phenytoinum (CYP3A4 isoenzyme substrate), amitriptyline and Cimetidinum. -
• Important clinical effects or changes of pharmacokinetics at the person at treatment were not observed mirtazapiny in combination with lithium.
Pharmakodinaminesky interaction
• Mirtazapin it is not necessary to apply in combination with inhibitors of a monoaminooxidase (MAO) or within two weeks after the treatment termination by MAO inhibitor.
• Mirtazapin can increase sedative properties of benzodiazepines and other sedatives. It is necessary to show care at purpose of these medicines together with mirtazapiny.
• Mirtazapin can strengthen the oppressing effect of alcohol on TsNS. Therefore patients have to be warned about need to avoid the use of alcoholic drinks.
• In case of use of other serotonergic medicines (for example, selective serotonin reuptake inhibitors, a venlafaksin) in combination with mirtazapiny, there is a risk of interaction which can lead to development of a serotoninovy syndrome that should be considered at selection of joint doses of drugs. Proceeding from post-registration experience of use of drug, it turned out that the serotoninovy syndrome arises very seldom at the patients receiving treatment mirtazapiny in combination with selective serotonin reuptake inhibitors or venlafaksiny.
• Mirtazapin in a dose of 30 mg caused small, but statistically significant increase in MHO (the International Normalized Relation) in the subjects receiving treatment by warfarin once a day. It is impossible to exclude more expressed effect at higher dose of a mirtazapin. It is recommended to control MHO in case of treatment by warfarin in combination with mirtazapiny.

Contraindications:

• Hypersensitivity to a mirtazapin or to any of excipients.
• As safety and efficiency for children up to 18 years are not established, it is not recommended to apply Mirtazonal to treatment of children.
• Pregnancy and the period of a lactation (efficiency and safety are not established).
With care
Correction of the mode of dosing and regular medical control are necessary for the following categories of patients:

• patients with epilepsy and organic lesions of a brain (against the background of therapy by drug Mirtazonal development of convulsive states is in rare instances possible);
• patients with a liver or renal failure;
• patients with heart diseases (conductivity disturbance, stenocardia or recently postponed myocardial infarction).
• patients with cerebrovascular diseases (including with the ischemic attacks in the anamnesis);
• patients with arterial hypotension and with the states contributing to hypotonia (including with dehydration and a hypovolemia);
• the patients abusing medicines with medicinal dependence, manias, hypomanias.
As well as other antidepressants, Mirtazonal it is necessary to apply with care in the following cases:
• Disturbance of an urination, including, at a prostate hyperplasia;
• acute closed-angle glaucoma and the increased intraocular pressure;
• diabetes mellitus.

Overdose:

Clinical safety of Mirtazonal at overdose was not investigated. Researches of toxicity testify to lack of clinically significant cardiotoxic action at overdose by drug.
Symptoms: the oppression of the central nervous system which is followed by a disorientation and long sedation in combination with tachycardia and insignificant hyper - or hypotension. However, there is a probability of heavier disturbances of physiological functions of an organism which can lead to a fatal outcome at the doses much exceeding a therapeutic dose, in particular at the mixed overdoses.
In case of overdose the symptomatic therapy directed to maintenance of the vital functions of an organism has to be carried out. Reception of absorbent carbon or a gastric lavage is recommended.

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children! Period of validity 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets for a rassasyvaniye of 15 mg, 30 mg, 45 mg.
On 6 tablets in A1/A1 strips or blisters. On 1, 3, 5, 6, 15 or 16 strips or blisters together with the application instruction in a cardboard pack.