Mirtazapin

General characteristics. Structure:

Active ingredient: миртазапин 15 mg, 30 mg, 45 mg.

excipients: a tablet kernel - lactose, starch corn, hydroxypropyl cellulose, silicon dioxide colloid anhydrous, magnesium stearate;

tablets on 15 mg a cover (opadr yellow) - a gipromelloza, titanium dioxide (E171), polyethyleneglycol 8000, ferrous oxide yellow (E172), quinoline yellow (Е 104), a yellow decline of FCF (Е 110);

tablets on 30 mg a cover (opadr beige) - a gipromelloza, titanium dioxide (E171), polyethyleneglycol 8000, ferrous oxide red (E172), ferrous oxide yellow (E172), ferrous oxide black (E172);

tablets on 45 mg a cover - a gipromelloza, titanium dioxide (E171), polyethyleneglycol 8000.

Pharmacological properties:

Pharmacodynamics. Active ingredient of drug Mirtazapin Sandoz — миртазапин — is an active central presynaptic antagonist α2-рецепторов which increases noradrenergichesky and serotonergic transfer to TsNS. Strengthening of serotonergic transfer happens only through 5-HT1-retseptory as миртазапин blocks 5-HT2-and 5-HT3-retseptory. Both enantiomer of a mirtazapin take part in this effect. S (+)-enantiomer blocks α2 and 5-HT2-retseptory, and R (-) - an enantiomer — 5-HT3-retseptory. Besides, миртазапин blocks H1 receptors that predetermines its sedative properties. In therapeutic doses practically does not show anticholinergic activity and does not influence cardiovascular system.

Pharmacokinetics. After oral administration миртазапин it is quickly and well soaked up (biological availability makes about 50%), reaching Cmax in a blood plasma approximately in 2 h. Nearly 85% of a mirtazapin contact proteins of a blood plasma. Average Т½ — 20–40 h; cases when Т½ made 65 h are recorded; shorter Т½ is usually observed at young patients. Longer Т½ allows to accept drug of 1 times a day. Stable concentration is reached in 3–4 days then accumulation takes place. Within the recommended dose pharmacokinetic indicators of a mirtazapin have linear dependence on the accepted drug dose. Meal does not influence pharmacokinetics of a mirtazapin.

Mirtazapin is actively metabolized and brought from an organism with urine and a stake for several days. The main ways of biotransformation are demethylation and oxidation with further conjugation. These in vitro (a liver microsome) specify that CYP 2D6 and CYP 1A2 enzymes of P450 cytochrome participate in formation 8 hydroxymetabolites of a mirtazapin, and CYP 3A4 creates N-dimetil-and N-oksidmetabolitov. N-dimetilmetabolit pharmacological is active and shows similar pharmacological action, as initial substance.

The clearance of a mirtazapin can decrease at a renal or liver failure.

Indications to use:

Treatment of a deep depression.

Route of administration and doses:

Adults. Effective daily dose usually 15–45 mg; an initial dose — 15 or 30 mg. If the initial dose makes 15 mg, and daily — 15 or 45 mg, apply tablets of the corresponding dosing. Mirtazapin begins to show effect after 1–2 weeks of treatment. Therapy by an adequate dose has to become the reason of affirmative answer for 2–4 weeks. At insufficient reaction the dose can be raised. If for the following 2–4 weeks of necessary effect do not reveal, drug should be cancelled. 

Patients of advanced age. The recommended dose is similar for adults. For the purpose of achievement of satisfactory and safe result, increase in a dose for patients of advanced age is carried out under strict control of the doctor.

Renal failure. The clearance of a mirtazapin can decrease at patients with a renal failure of moderate or heavy degree (clearance of creatinine <40 ml/min.). Appointing Mirtazapin Sandoz of this category of patients, it is necessary to control clearance of creatinine.

Liver failure. The clearance of a mirtazapin can decrease at patients with a liver failure. This fact needs to be considered, appointing Mirtazapin Sandoz of this category of patients, especially with a liver failure of heavy degree. Appoint Mirtazapin Sandoz, since the minimum dose and controlling clearance of a mirtazapin, especially in case of increase in a dose.

Т½ a mirtazapina of 20-40 h therefore it is possible to apply it 1 time a day.

It is desirable to use drug in at one time, for the night before going to bed. The daily dose of drug can be divided into 2 receptions (in the morning and in the evening; the most part of a dose should be accepted for the night).

Tablets should be applied inside, to swallow, without chewing; if necessary — to wash down with water.

Patients with a depression are treated throughout the long period, by not less than 6 months, before total disappearance of symptoms.

It is recommended to stop treatment mirtazapiny gradually, in order to avoid cancellation symptoms.

Features of use:

Suicide / suicide thoughts or clinical deterioration. The depression is connected with the increased risk of suicide thoughts, drawing to itself harm, a suicide (the cases connected with a suicide). This risk is noted before emergence of the expressed remission. As improvement can not occur for the first weeks or more treatment, patients have to be under strict control of the doctor before improvement. According to the general clinical experience, the risk of a suicide can increase at early stages of recovery.

It is known that patients with suicide attempts in the anamnesis, or patients who show the expressed degree of suicide thinking even prior to therapy have high risk of emergence of suicide thoughts or attempts of suicide and have to be under strict control throughout all treatment. The analysis of clinical trials of antidepressants which are applied by adults with mental disorders, confirms the increased risk of development of suicide behavior at reception of antidepressants in comparison with patients aged <25 years which received placebo.

During therapy by antidepressants strict control of patients with high risk of suicide behavior, especially at the beginning of therapy and after dosing change is necessary. Patients should be warned about need to pay attention to any clinical manifestations, suicide behavior or thoughts and unusual changes in behavior and to address for medical recommendations immediately if such symptoms arose. 

In view of a possibility of suicide, especially in an initiation of treatment, the patient needs to give minimum necessary quantity of tablets of drug.

Oppression of activity of marrow. During treatment mirtazapiny it was reported about oppression of activity of marrow that it is usually shown by a granulocytopenia or an agranulocytosis. 

It was reported about separate cases of an agranulocytosis, they are usually reversible, but sometimes — with lethal effects (it is preferential at patients aged> 65 years). The doctor has to pay attention to such symptoms as fever, a pharyngalgia, stomatitis or other symptoms of an infection. When there are such symptoms, treatment should be stopped and made blood test.

Jaundice. Treatment needs to be stopped at emergence of jaundice.

States at which strict control of the doctor is necessary. Careful dosing, and also regular and careful observation are necessary for patients with the following states:

 

epilepsy and organic lesions of a brain. Mirtazapin patients should apply with extra care with epileptic attacks in the anamnesis. Treatment should be stopped to patients at whom epileptic attacks develop or when note increase in frequency of epileptic attacks;

liver failure: after oral administration of 15 mg of a mirtazapin its clearance decreases approximately by 35% at patients with a liver failure of easy or moderate weight in comparison with patients with normal function of a liver. Average plasma concentration of a mirtazapin increases approximately by 55%. Appointing 30 mg of a mirtazapin, it is necessary to consider a ratio advantage / potential risk for the patient;

renal failure: after single oral administration of 15 mg of a mirtazapin by patients with a renal failure of moderate degree (10 ml/min. ≤ clearance of creatinine <40 ml/min.) or heavy degree (the clearance of creatinine <10 ml/min.) clearance of a mirtazapin decreased approximately by 30 and 50% respectively in comparison with healthy patients. Average concentration of a mirtazapin in a blood plasma increased by 55 and 115% respectively. Patients had no considerable differences with a renal failure of easy degree (40 ml/min. ≤ clearance of creatinine <80 ml/min.) in comparison with control group. Appointing 30 mg of a mirtazapin, it is necessary to consider a ratio advantage / potential risk for the patient and to control clearance of creatinine;

heart diseases, such as conductivity disturbance, stenocardia and recently postponed myocardial infarction. In these the accompanying therapy it is necessary to appoint cases with care;

arterial hypotension;

diabetes mellitus: at patients with a diabetes mellitus antidepressants can influence glucose level in blood. There can be a need for dose adjustment of insulin and/or peroral hypoglycemic drugs and careful observation is recommended.

As well as at use of other antidepressants, it is necessary to take the following into account:

 

at use of antidepressants for patients with schizophrenia or other mental disorders psychotic symptoms can become aggravated; paranoid thoughts can become more intensive;

at treatment of a depressive phase of bipolar disorder it can pass into a maniacal phase. It is necessary to observe carefully patients with maniacal or hypomaniacal manifestations in the anamnesis. Use of a mirtazapin should be stopped if the patient enters a maniacal phase;

though accustoming to drug does not arise, post-marketing experience of use shows that the sudden termination of treatment after long use can sometimes lead to emergence of symptoms of cancellation. The majority of reactions of cancellation are shown by insignificant clinical symptoms and take place. Among different symptoms there are cancellations about which it was reported, dizziness, excitement, concern, a headache and nausea were the most frequent. Though about them it was reported as about cancellation symptoms, it is necessary to remember that they can be connected with the course of a basic disease. It is recommended to stop gradually treatment mirtazapiny;

care at treatment of patients with disorders of urination is necessary including as the investigations of a prostatauxe, patients with acute closed-angle glaucoma and the increased intraocular pressure (however drug influence Mirtazapin Sandoz is improbable owing to his very low anticholinergic activity);

akathisia / psychomotor excitement: use of antidepressants is connected with development of an akathisia that it was characterized by subjectively unpleasant or alarming excitement and need often to move together with impossibility quietly to sit or stand. Most likely, these symptoms can arise for the first several weeks of treatment therefore increase in a dose can damage health.

Hyponatremia. There were separate messages on a hyponatremia at use of a mirtazapin that is connected with inadequate secretion of antidiuretic hormone. The patients of advanced age or persons applying the accompanying therapy which can cause a hyponatremia demand special control.

Serotoninovy syndrome. Interaction with serotonergic active agents: the serotoninovy syndrome can arise when selective serotonin reuptake inhibitors apply combined with other serotonergic active agents. The hyperthermia, muscle tension, a myoclonia, autonomous instability with possible bystry fluctuations of the vital indicators can be symptoms of a serotoninovy syndrome. Changes of a mental state include confusion of consciousness, annoyance and high excitement which progresses to a delirium and a coma. The Serotoninovy syndrome arises very seldom at patients who receive treatment only mirtazapiny.

Patients of advanced age. Appointing миртазапин to patients of advanced age, it is necessary to remember undesirable effects which are shown against the background of use of antidepressants. Emergence of side reactions at elderly people was noted not more often than at patients of other age categories.

Lactose. Drug contains lactose therefore patients should not appoint it with the most rare hereditary forms of intolerance of a galactose, deficit of lactase or a syndrome of glyukozo-galaktozny malabsorption.

Use during pregnancy and feeding by a breast. Safety and efficiency of use of a mirtazapin during pregnancy are not established therefore it is not necessary to appoint drug pregnant. It is unknown whether gets миртазапин into breast milk therefore during treatment feeding by a breast should be stopped.

Children. Drug is not used for treatment of children. The behavior connected with a suicide (attempts of suicide and suicide thoughts), hostility (preferential aggression, oppositional behavior and anger) most often was revealed among children and teenagers who were treated antidepressants. If, based on clinical need, the decision on therapy was made by antidepressants — the patient needs to be observed carefully in connection with possible emergence of suicide symptoms. Besides, the uses for children and teenagers given on safety in a growth period, maturing, cognitive and behavioral development are absent.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Drug influences ability to manage vehicles and to work with other mechanisms — concentration of attention can worsen (especially at an initial stage of treatment). The patients applying Mirtazapin Sandoz should avoid performance of potentially dangerous types of activity which demand concentration of attention.

Side effects:

At patients with a depression symptoms which can be connected with the disease were revealed. However it is sometimes difficult to define what symptoms are display of a disease and what — result of treatment mirtazapiny.

The most widespread side reactions which arise at more than 5% of patients who are treated mirtazapiny: drowsiness, sedation, dryness in a mouth, increase in body weight, increase in appetite, dizziness and increased fatigue.

Side effects are classified by the frequency of manifestations: very often (≥1/10), it is frequent (≥1/100, <1/10), infrequently (≥1/1000, <1/100), is rare (≥1/10 000, <1/1000), frequency is unknown (side reactions from spontaneous reports).

From blood and lymphatic system: frequency is unknown — oppression of activity of marrow (a granulocytopenia, an agranulocytosis, aplastic anemia, thrombocytopenia), an eosinophilia.

Metabolism and disturbance of food: very often — increase in body weight, increase in appetite; frequency is unknown — a hyponatremia.

Mental disturbances: often — a sleep disorder, confusion of consciousness, concern, sleeplessness; sometimes — nightmares, a mania, agitation, hallucinations, psychomotor excitement (including an akathisia, a hyperkinesia); frequency is unknown — suicide thoughts, behavior. 

From TsNS: very often — drowsiness, sedation, a headache; often — a lethargy, dizziness, a tremor; sometimes — paresthesia, increased fatigue of legs, a syncope; seldom — a myoclonia; frequency is unknown — spasms (hemorrhage), a serotoninovy syndrome, paresthesias of a mucous membrane of an oral cavity.

Vascular disorders: often — orthostatic hypotension; sometimes — arterial hypotension.

From a GIT: very often — dryness in a mouth; often — nausea, diarrhea, vomiting; sometimes — a hypesthesia of a mucous membrane of an oral cavity; frequency is unknown — hypostasis of a mucous membrane of an oral cavity. 

From gepatobiliarny system: seldom — increase in activity of transaminases in blood serum.

From skin and hypodermic cellulose: often — a dieback; frequency is unknown — Stephens's syndrome — Johnson; violent dermatitis; multiformny erythema; toxic epidermal necrolysis.

From a musculoskeletal system and connecting fabric: often — an arthralgia, a mialgiya, a dorsodynia.

From endocrine system: frequency is unknown — disturbance of secretion of antidiuretic hormone. 

General disturbances: often — peripheral hypostases, increased fatigue.

It should be noted that the dose decline usually does not lead to drowsiness reduction / седатации, but can reduce efficiency of antidepressant.

Excitement and sleeplessness which can be depression symptoms can worsen owing to treatment by antidepressants, including mirtazapiny.

Cases of suicide thoughts and behavior noted throughout therapy mirtazapiny or after the treatment termination.

Revealed temporary increase in level of transaminase and a γ-glutamiltransferaza (however it was not reported about side reactions).

Interaction with other medicines:

Pharmakodinamichesky interactions 

Mirtazapin it is not necessary to accept along with MAO inhibitors or for 2 weeks after the end of therapy. After completion of treatment mirtazapiny there have to pass about 2 weeks before patients are able to apply MAO inhibitors.

Besides, the concomitant use of a mirtazapin with selective serotonin reuptake inhibitors and others active agents (L-tryptophane, triptane, трамадол, линезолид, венлафаксин, the lithium and drugs containing a St. John's Wort (Hypericum perforatum)) can lead serotoninergicheskimiya to emergence of the effects caused by serotonin. At the combined use of these active agents with mirtazapiny it is recommended to be careful and be under strict medical observation.

Mirtazapin can increase sedative properties of benzodiazepines and other sedative drugs (in particular the majority of anti-psychotics, antagonists of H1 receptors, opioids). 

Mirtazapin Sandoz can strengthen depressive effect of alcohol on TsNS therefore patients should refrain from alcohol intake for treatment by drug.

Mirtazapin in a dose of 30 mg of 1 times a day causes small, but statistically significant increase in the international normalized index in patients who were treated warfarin. It is recommended to control it in case of the accompanying use of warfarin with mirtazapiny in connection with its possible increase.

Pharmacokinetic interactions 

Carbamazepine and Phenytoinum, the inductors CYP 3A4 increase clearance of a mirtazapin approximately twice and, as a result, average concentration of a mirtazapin in a blood plasma decreases by 60 and 45% respectively. When carbamazepine or any other inductor of hepatic metabolism (for example rifampicin) add to therapy mirtazapiny, the dose of the last should be raised. If treatment by such drug stops, there can be a need for a dose decline of a mirtazapin.

The accompanying use of powerful CYP 3A4 inhibitor of a ketokonazol raised Cmax in a blood plasma and AUC of a mirtazapin approximately for 40 and 50% respectively.

At use of Cimetidinum (weak CYP 1A2, CYP 2D6 and CYP 3A4 inhibitor) with mirtazapiny average plasma concentration of a mirtazapin can increase more than by 50%. It is necessary to lower a dose at the combined use of a mirtazapin with powerful CYP 3A4 inhibitors, HIV protease inhibitors, azolny antifungal means, erythromycin, Cimetidinum or nefazodony.

Any clinically significant pharmacokinetic interaction at simultaneous use of a mirtazapin with paroksetiny, amitriptyline, risperidony or lithium is not revealed.

Contraindications:

Hypersensitivity to a mirtazapin or to any component of drug. Simultaneous use of a mirtazapin with MAO inhibitors.

Overdose:

Experience concerning overdose mirtazapiny demonstrates that symptoms of easy degree noted. It was reported about oppression of TsNS with a disorientation and a long sedatation that was followed by tachycardia and insignificant arterial hypo - or hypertensia. However more serious consequences are possible (including lethal) at use in a dose, is much higher therapeutic, especially at the mixed overdoses.

At overdose patients should carry out the corresponding symptomatic therapy and to support vital signs of an organism. It is possible to apply absorbent carbon or to make a gastric lavage.

Storage conditions:

Does not demand special storage conditions.

Issue conditions:

According to the recipe

Packaging:

Tablets п / captivity. cover of 15 mg blister, No. 20

Tablets п / captivity. cover of 30 mg blister, No. 20

Tablets п / captivity. cover of 45 mg blister, No. 20