Mirtazapine Canon - instructions for use, dose, side effects, contraindications

Excipients: corn starch 40 mg, croscarmellose sodium 6.5 mg, mannitol 33 mg, magnesium stearate 1 mg, povidone 7 mg, microcrystalline cellulose 37.5 mg;

composition of film shell: Opadrai II purple 4 mg, including: polyvinyl alcohol 1,6 mg, macrogol (polyethylene glycol) 0.808 mg, talc 0.592 mg, titanium dioxide 0.6 mg, dye indigo carmine 0.24 mg, dye crimson [Ponso 4R] 0.16 mg.

Dosage of 30 mg

1 tablet, film-coated, contains:

active substance: mirtazapine 30 mg, in the form of mirtazapine hemihydrate 31 mg;

Excipients: starch corn 80 mg, croscarmellose sodium 13 mg, mannitol 66 mg, magnesium stearate 2 mg, povidone 14 mg, cellulose microcrystalline 75 mg;

composition of film shell: Opaprai II purple 8 mg, including: polyvinyl alcohol 3.2 mg, macrogol (polyethylene glycol) 1.616 mg, talc 1.184 mg, titanium dioxide 1.2 mg, indigo carmine dye 0.48 mg, dye crimson [Ponso 4R] 0.32 mg.

Dosage of 45 mg

1 tablet, film-coated, contains:

active substance: mirtazapine 45 mg, in the form of mirtazapine hemihydrate 46.5 mg;

Excipients: corn starch 120 mg, croscarmellose sodium 19.5 mg, mannitol 99 mg, magnesium stearate 3 mg, povidone 21 mg, microcrystalline cellulose 112.5 mg;

composition of film shell: Opaprai II purple 12 mg, including: polyvinyl alcohol 4.8 mg, macrogol (2.41 mg), talc 1.776 mg, titanium dioxide 1.8 mg, indigo carmine dye 0.72 mg, dye crimson [Ponso 4R] 0.48 mg.

Description:

Round, biconvex tablets, covered with a film shell of purple.On the cross-section - almost white.

Pharmacotherapeutic group:antidepressant

ATX: & nbsp

N.06.A.X.11 Mirtazapine

Pharmacodynamics:

Pharmacological properties

Mirtazapine is an antidepressant of a tetracyclic structure with a predominantly sedative effect. The drug is most effective in depressive states with symptoms in the clinical picture such as inability to experience pleasure and joy, loss of interest (anhedonia), psychomotor retardation, sleep disorders (especially in the form of early awakenings) and weight loss, as well as other symptoms: suicidal thoughts and daily mood swings.

The antidepressant effect of the drug usually comes in 1-2 weeks of treatment.

Pharmacodynamics

Mirtazapine is an antagonist of presynaptic α₂adrenoreceptors in the central nervous system and enhances central noradrenergic and serotonergic transmission of nerve impulses. In this case, the enhancement of serotonergic transmission is realized only through 5-HT₁-receptors, since mirtazapine blocks 5-HT₂- and 5-HT₃-receptors. It is believed that both enantiomers of mirtazapine have antidepressant activity, S(+) - enantiomer - by blocking α₂- and 5-HT₂-receptors, and R(-) - enantiomer - by blocking 5-HT₃-receptors.

Sedative properties of mirtazapine are due to its antagonistic activity in relation to H₁-histamine receptors.

Mirtazapine is usually well tolerated. Virtually does not possess m-cholinoblocking activity and in therapeutic doses has a limited effect on the cardiovascular system (eg, orthostatic hypotension).

Pharmacokinetics:

Suction

After oral administration of the drug mirtazapine quickly absorbed (bioavailability of about 50%), reaching a maximum concentration in the blood plasma after about 2 hours.

Distribution

About 85% of mirtazapine binds to plasma proteins. Stable concentration of the substance is achieved after 3-4 days and in the future it does not change. In the recommended dosage range, the pharmacokinetic parameters of mirtazapine are linearly dependent on the administered dose of the drug.

Metabolism

Mirtazapine is actively metabolized. The main ways of its metabolism in the body are demethylation and oxidation followed by conjugation. Cytochrome P450-dependent isozymes CYP2D6 and CYP1A2 are involved in the formation of 8-hydroxy metabolite mirtazapine, while isoenzyme CYP3A4, presumably, determines the formation N-detylated and Noxidized metabolites.Demethylmirtazapine is pharmacologically active and appears to be pharmacokinetically similar to the parent compound.

Excretion

Mirtazapine is excreted by the kidneys and through the intestine for several days. The average half-life is between 20 and 40 hours (rarely up to 65 hours). A shorter half-life is observed in young people.

The clearance of mirtazapine decreases with renal or hepatic insufficiency.

Indications:

Depressive states (including anhedonia, psychomotor retardation, insomnia, early awakening, weight loss, loss of interest in life, suicidal thoughts and mood lability).

Contraindications:

- Hypersensitivity to mirtazapine or other components of the drug;

- age under 18 years (effectiveness and safety not established);

- simultaneous administration with monoamine oxidase (MAO) inhibitors.

Carefully:

Correction of the dosing regimen and regular medical supervision are necessary for the following categories of patients:

- in patients with epilepsy and organic lesions of the brain (on the background of drug therapy in rare cases, the development of convulsive conditions);

- in patients with hepatic or renal insufficiency;

- in patients with heart disease (conduction disorders, angina pectoris or recent myocardial infarction);

- in patients with cerebrovascular diseases (including ischemic attacks in the anamnesis);

- in patients with arterial hypotension and conditions predisposing to hypotension (including dehydration and hypovolemia);

- in patients who abuse drugs, with drug dependence, mania, hypomania.

Like other antidepressants, mirtazapine should be used with caution in the following cases:

- disorders of urination, including with prostatic hyperplasia;

- acute angle-closure glaucoma and increased intraocular pressure;

- diabetes;

- hyponatremia.

Pregnancy and lactation:

The safety of mirtazapine during pregnancy is not established, therefore, the Mirtazapine Canon preparation should be prescribed during pregnancy only if the benefit to the mother exceeds the potential risk to the fetus, treatment should be controlled by the doctor.The use of serotonin reuptake inhibitors in pregnancy, especially in later stages, may increase the risk of developing persistent pulmonary hypertension in newborns.

It is not known whether mirtazapine with breast milk, so the use of Mirtazapine canon during breastfeeding is not recommended.

Dosing and Administration:

Tablets should be taken orally, without chewing, with a small amount of water. Eating does not affect the pharmacokinetics of the drug.

The half-life period of mirtazapine is 20-40 hours and therefore the drug is suitable for reception once a day. It is preferable to take a daily dose of the drug at one time, before going to sleep at night. Mirtazapine can also be prescribed for admission twice a day, dividing the daily dose in half (morning and night).

Treatment with Mirtazapine canon should be continued for as long as possible for 4-6 months until the symptoms disappear completely. After this treatment can be gradually canceled. The drug begins to have its effect after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response in 2-4 weeks.With an insufficient response to treatment, the dose can be increased to the maximum dose (45 mg). In the absence of response to treatment after 2-4 weeks treatment should be discontinued.

Adults

The recommended initial daily dose is 15 mg / day or 30 mg / day, which is gradually increased if necessary to 45 mg / day.

Elderly

The recommended dose is the same as for adults. In elderly patients, in order to achieve a satisfactory and safe response to treatment, an increase in the dose should be made under the direct supervision of a physician.

Patients with renal and hepatic insufficiency

In patients with renal or hepatic insufficiency, the clearance of mirtazapine may be reduced. This should be taken into account when prescribing a drug in this category of patients.

Side effects:

Patients with depression experience a number of symptoms due to the disease, so it is sometimes difficult to distinguish between symptoms associated with the disease and symptoms caused by the use of the drug.

When using the drug, there may be side effects.

Classification of WHO frequency of development of side effects

very often - ≥1/10 appointments (> 10%)

often from ≥1 / 100 to <1/10 of appointments (> 1% and <10%)

infrequently - from ≥1 / 1000 to <1/100 of prescriptions (> 0.1% and <1%)

rarely from ≥1 / 10000 to <1/1000 appointments (> 0.01% and <0.1%)

very rarely - <1/10000 prescriptions (<0.01%)

frequency is unknown - according to available data, it is not possible to establish the frequency of occurrence

Violations of the blood and lymphatic system

The frequency is not established: oppression hemopoiesis (granulocytopenia, agranulocytosis, aplastic anemia and thrombocytopenia), eosinophilia.

Disorders from the endocrine system

The frequency is unknown: a violation of the secretion of antidiuretic hormone.

Disorders from the metabolism and nutrition

Very often: increased appetite and weight gain.

Frequency unknown: hyponatremia.

Disturbances from the nervous system

Very often: drowsiness (can lead to impaired concentration) is more common in the first weeks of treatment (lowering the dose usually does not lead to a decrease in sedation, but may decrease the effectiveness of the antidepressant), sedation, headache.

Often: lethargy, dizziness, tremor.

Infrequently: paresthesia, restless leg syndrome, fainting.

Rarely: myoclonus.

The frequency is unknown: convulsions, serotonin syndrome, paresthesia of the oral mucosa, articulation disorder.

Disorders of the psyche

Often: unusual dreams, confusion, anxiety *, insomnia *.

Infrequently: nightmares, mania, agitation, hallucinations, psychomotor agitation (including akathisia, hyperkinesia).

Rarely: aggressiveness.

The frequency is unknown: suicidal thoughts, suicidal behavior.

Vascular disorders

Often: orthostatic hypotension.

Infrequent: lowering blood pressure.

Disorders from the gastrointestinal tract

Very often: dry mouth.

Often: nausea, vomiting, diarrhea.

Infrequently: hypoesthesia of the oral mucosa.

The frequency is unknown: edema of the oral mucosa, increased salivation.

Disturbances from the liver and bile ducts

Rarely: increased activity of "liver" enzymes.

Disorders from the rut and subcutaneous tissues

Often: skin rash.

The frequency is unknown: Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, toxic epidermal necrolysis.

Disturbances from musculoskeletal and connective tissue

Often: back pain, arthralgia, myalgia.

General disorders and disorders at the site of administration

Often: local edema.

Uncommon: fatigue.

Frequency unknown: generalized or local edema.

* Usually, when treated with antidepressants, anxiety and insomnia (which may be symptoms of depression) may develop or worsen. In the treatment of mirtazapine, the development or worsening of anxiety has been reported very rarely.

A temporal increase in the level of transaminases and gamma-glutamyltranspeptidase was observed in the evaluation of clinical trial data (however, no adverse reactions associated with mirtazapine were reported, which occurred more frequently than with placebo).

In addition, the following adverse reactions can occur: withdrawal syndrome, hives, thirst.

Overdose:

Toxicity studies indicate that there is no clinically significant cardiotoxic effect with drug overdose.

Symptoms: Oppression of the central nervous system, accompanied by disorientation and prolonged sedation, hallucinations, tachycardia, moderate increase or decrease in blood pressure.There is a possibility of more serious violations of the physiological functions of the body, which can lead to a fatal outcome at doses far exceeding the therapeutic dose, especially with mixed overdoses.

Treatment: In case of an overdose, symptomatic therapy should be conducted, aimed at maintaining the vital functions of the body. It is recommended to take activated charcoal, wash the stomach.

Interaction:

Pharmacokinetic interaction

Mirtazapine is extensively metabolized with the participation of isoenzymes CYP2D6 and CYP3A4, and to a lesser extent with the participation of isoenzyme CYP1A2. Study of the interaction of mirtazapine with paroxetine in healthy volunteers showed that paroxetine, which is an inhibitor of the isoenzyme CYP2D6, does not affect the pharmacokinetics of mirtazapine in the equilibrium state. The use of mirtazapine in combination with a potent inhibitor of isoenzyme CYP3A4, ketoconazole, increased the maximum plasma concentration levels and the area under the concentration-time curve of mirtazapine by approximately 40% and 50%, respectively. Caution should be exercised when using mirtazapine in combination with potent inhibitors of isoenzyme CYP3A4, such as HIV protease inhibitors, azole antifungal drugs, erythromycin or nefazodone.

Carbamazepine and phenytoin, isoenzyme inducers CYP3A4, increased the clearance of mirtazapine approximately twice, which resulted in a 45-60% decrease in the concentrations of mirtazapine in plasma. When adding carbamazepine or another inducer of hepatic metabolism (eg rifampicin) to mirtazapine therapy, the dose of mirtazapine may need to be increased. When discontinuing treatment with such a drug, it may be necessary to reduce the dose of mirtazapine.

When the drug is used in combination with cimetidine, the bioavailability of mirtazapine may increase by more than 50%. The dose of mirtazapine may be reduced at the start of treatment in combination with cimetidine or increased with cimetidine discontinuation.

In studies in vivo mirtazapine had no effect on the pharmacokinetics of risperidone or paroxetine (substrate isoenzyme CYP2D6), carbamazepine and phenytoin (substrate isoenzyme CYP3A4), amitriptyline and cimetidine.

With the combined use of mirtazapine in combination with lithium, no pronounced clinical effects were observed, as well as changes in the pharmacokinetics of both drugs.

Pharmacodynamic interaction

Mirtazapine should not be used in combination with monoamine oxidase (MAO) inhibitors or within two weeks after discontinuation of treatment with MAO inhibitors. Treatment with MAO inhibitors should begin no earlier than 2 weeks after discontinuation of treatment with mirtazapine.

Mirtazapine can enhance the sedative properties of benzodiazepines and other sedatives (in particular the majority of antipsychotics, antagonists H₁histamine receptors, opioids).

Mirtazapine can enhance the depressant effect of alcohol on the central nervous system, so patients should be warned about the need to avoid drinking alcohol.

Simultaneous reception with other serotonergic drugs (for example, L-tryptophan, tryptane, tramadol, linezolid, selective serotonin reuptake inhibitors, venlafaxine, lithium preparations, St. John's wort preparations (perforated (Hypericum perforatum)) can lead to the development of serotonin syndrome (see section "Special instructions").

Mirtazapine at a dose of 30 mg once a day caused a small but statistically significant increase in INR (International Normalized Ratio) in patients treated with warfarin.You can not exclude a more pronounced effect with a higher dose of mirtazapine. It is recommended to monitor INR in case of treatment with warfarin in combination with mirtazapine.

Special instructions:

Suicide / suicidal thoughts or clinical worsening of the course of the disease. In young people (under 24 years) with depression and other mental disorders, antidepressants, compared with placebo, increase the risk of suicidal thoughts and suicidal behavior, so when prescribing Mirtazapine canon, such patients should correlate the risk of suicide and the benefit of using the drug. In short-term studies in people over 24 years of age, the risk of suicide did not increase, and in patients older than 65 years, it declined slightly.

Any depressive disorder in itself increases the risk of suicide, so during treatment for the patient, surveillance should be established to detect abnormalities or changes in behavior, as well as suicidal tendencies. Given the possibility of suicide, especially at the beginning of treatment, the patient should be given the least amount of tablets to reduce the risk of overdose.

Inhibition of bone marrow function. Oppression of bone marrow functions, usually manifested in the form of granulocytopenia or agranulocytosis, is rarely observed with mirtazapine, appears mostly after 4-6 weeks of treatment and reversibly after discontinuation of treatment. The doctor should carefully (and inform the patient) to symptoms such as fever, sore throat, stomatitis and other signs of flu-like syndrome. When these symptoms appear, stop treatment and make a blood test.

Jaundice. When there are signs of jaundice, Mirtazapine canon should be discontinued.

Conditions requiring medical attention. The drug should be administered with caution, as well as regular and careful monitoring of patients under the following conditions:

- Epilepsy and organic lesions of the brain. Although clinical experience shows that epileptic seizures occur rarely both in the treatment of mirtazapine and in the treatment of other antidepressants, the Mirtazapine Canon preparation should be used with caution in patients with epileptic seizures in the anamnesis.

- Liver failure. With oral administration of mirtazapine at a dose of 15 mg, the clearance of mirtazapine decreased by approximately 35% in patients with hepatic insufficiency of mild or moderate severity compared with patients with normal liver function. The average concentration of mirtazapine in blood plasma increased by approximately 55%.

- Renal failure. When oral administration of mirtazapine at a dose of 15 mg in patients with moderate renal insufficiency (creatinine clearance 10-40 ml / min) or severe (creatinine clearance less than 10 ml / min), the clearance of mirtazapine decreased by approximately 30% and 50% compared with healthy patients. The average concentration of mirtazapine in blood plasma increased by 55% and 115%, respectively. In patients with mild renal insufficiency (creatinine clearance 40-80 ml / min), there were no significant differences in comparison with the control group.

- Heart diseases such as conduction disorders, angina pectoris and recent myocardial infarction. In these cases, the usual precautions are necessary when prescribing Mirtazapine Kanon and concomitant therapy.

- Reduced blood pressure.

- Diabetes. In patients with diabetes, antidepressants can affect blood glucose levels. You may need to adjust the dose of insulin and / or a dose of oral hypoglycemic drugs. Careful observation is recommended.

As with other antidepressants, the following conditions may occur with the use of the Mirtazapine Canon preparation:

- Worsening of psychotic symptoms can occur in the application of antidepressants for the treatment of patients with schizophrenia and other mental disorders. Paranoid ideas can intensify.

- The depressive phase of bipolar disorder during treatment can transform into the manic phase.

- Despite the fact that antidepressants are not addictive, post-marketing on the basis of experience, it appears that abrupt withdrawal of treatment after prolonged use can cause symptoms of "lifting". Most of the symptoms of "withdrawal" are weak and self-limiting. The most frequently reported symptoms following "cancellation": dizziness, nausea, headache and malaise, agitation, anxiety.Although these symptoms have been reported as symptoms of "withdrawal", it should be understood that these symptoms can be associated with a major disease. It is recommended to stop the treatment with Mirtazapine Canon gradually.

- Mirtazapine canon should be administered with caution to patients with urinary dysfunction, incl. with hypertrophy of the prostate, as well as patients with acute closed-angle glaucoma and increased intraocular pressure (however, the adverse effect of the drug is unlikely because the anticholinergic activity of mirtazapine is very poorly expressed).

- Akathisia / psychomotor agitation. The use of antidepressants is associated with the development of akathisia, which is characterized by subjectively unpleasant or anxious anger with increased motor activity. Most likely, the appearance of such symptoms during the first few weeks of treatment. Increasing the dose in this case can have a negative impact on the patient's health.

- Hyponatremia. When using mirtazapine, extremely rare cases of hyponatremia are described. Patients at risk (elderly or patients taking drugs,which can cause hyponatremia), the drug Mirtazapine canon should be administered with caution.

- Serotonin syndrome. With the simultaneous use of selective serotonin reuptake inhibitors and other serotonergic drugs, serotonin syndrome may occur. Symptoms of serotonin syndrome can be: fever, rigidity, myoclonus, autonomic nervous system disorder with possible rapid fluctuations in vital signs of the functional state of the organism, changes in mental state, including confusion, irritability and strong arousal, progressive disorder of consciousness and to whom. Care should be taken and careful clinical monitoring is carried out while taking these drugs with mirtazapine. If such symptoms appear, stop using Mirtazapine Kanon and begin symptomatic treatment. Based on the post-registration experience, it turned out that serotonin syndrome occurs very rarely in patients who receive monotherapy with mirtazapine.

- Use in elderly patients.Elderly patients are usually more sensitive, especially with regard to side effects. In clinical studies, it has not been noted that elderly patients experience side effects more often than in other age groups, but they may be more pronounced, but the data is still limited.

- Patients are advised to avoid the use of alcohol in the treatment with Mirtazapine Canon.

- Caution should be used when prescribing benzodiazepines simultaneously with mirtazapine.

Effect on the ability to drive transp. cf. and fur:

During treatment with Mirtazapine, the Canon should avoid performing potentially dangerous activities requiring high rates of psychomotor reactions, such as motor vehicle management or other mechanisms.

Form release / dosage:

Film-coated tablets, 15 mg, 30 mg and 45 mg.

Packaging:

For tablets with a dosage of 15 mg and 30 mg: on 10 or 30 tablets in a contour cellular package from a film of polyvinylchloride and a foil of aluminum printed varnished. According to 1, 2, 3, 6 contour cell packs of 10 tablets or 1, 2 circuit cell packs of 30 tablets together with the instruction for use are placed in a pack of cardboard.

For tablets with a dosage of 45 mg: on 10 or 15 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

According to 1, 2, 3, 6 contour cell packs of 10 tablets or 2, 4 contour cell packs of 15 tablets together with instructions for use are placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002195

Date of registration:22.08.2013 / 27.12.2013

Expiration Date:22.08.2018

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp05.09.2016

Illustrated instructions

Instructions

Mirtazapine Canon (Mirtazapine Canon)