The antidepressants mirtazapine. New generation antidepressant Mirtazapine: indications, instructions, reviews

N.06.A.X.11 Mirtazapine

Pharmacological properties

Mirtazapine is a tetracyclic antidepressant with a predominantly sedative effect. The drug is most effective in depressive conditions with the presence of clinical picture symptoms such as inability to experience pleasure and joy, loss of interest (anhedonia), psychomotor retardation, sleep disturbances (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 occurs after 1-2 weeks of treatment.

Pharmacodynamics

Mirtazapine is an antagonist of presynaptic α 2 -adrenergic receptors in the central nervous system and enhances central noradrenergic and serotonergic transmission of nerve impulses. In this case, an increase in serotonergic transmission is realized only through 5-HT 1 receptors, since it blocks 5-HT 2 and 5-HT 3 receptors. It is believed that both enantiomers of mirtazapine have antidepressant activity, the S (+) enantiomer - blocking α 2 - and 5-HT 2 -receptors, and R (-) - enantiomer - blocking 5-HT 3 -receptors.

The sedative properties of mirtazapine are due to its antagonistic activity towards H 1 -histamine receptors.

Mirtazapine is generally well tolerated. It has practically no m-anticholinergic activity and, in therapeutic doses, has a limited effect on the cardiovascular system (for example, orthostatic hypotension).

Suction

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

Distribution

About 85% of mirtazapine binds to plasma proteins. A stable concentration of the substance is reached after 3-4 days and does not change in the future. In the recommended dose range, the pharmacokinetic parameters of mirtazapine have a linear dependence on the administered dose of the drug.

Metabolism

Mirtazapine is extensively metabolized. The main pathways of its metabolism in the body are demethylation and oxidation followed by conjugation. Cytochrome P450-dependent isoenzymes CYP 2D 6 and CYP 1A 2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, while the isoenzyme CYP 3A 4 presumably determines the formation of N-demethylated and N-oxidized metabolites. Demethylmirtazapine is pharmacologically active and appears to be pharmacokinetically similar to the parent compound.

Withdrawal

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

The clearance of mirtazapine is reduced in renal or hepatic insufficiency.

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

Hypersensitivity to mirtazapine or other components of the drug;

Age up to 18 years (efficacy and safety have not been established);

Simultaneous reception with monoamine oxidase inhibitors (MAO).

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

In patients with epilepsy and organic brain lesions (against the background of drug therapy, in rare cases, the development of convulsive states is possible);

In patients with hepatic or renal impairment;

In patients with heart disease (conduction disturbances, angina pectoris, or recent myocardial infarction);

In patients with cerebrovascular diseases (including a history of ischemic attacks);

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

In patients who abuse medicines, with drug addiction, mania, hypomania.

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

Violation of urination, including hyperplasia prostate;

Acute angle-closure glaucoma and increased intraocular pressure;

Diabetes;

Hyponatremia.

The safety of using mirtazapine during pregnancy has not been established, therefore, the drug Mirtazapine Canon should be prescribed during pregnancy only in cases where the benefit to the mother outweighs the potential risk to the fetus, treatment should be carried out under the supervision of a physician. The use of serotonin reuptake inhibitors during pregnancy, especially on later stages may increase the risk of developing persistent pulmonary hypertension in neonates.

It is not known whether it stands out with breast milk, therefore, the use of the drug Mirtazapine Canon during breastfeeding is not recommended.

The tablets should be taken orally, without chewing, with a little water. Food intake does not affect the pharmacokinetics of the drug.

The half-life of mirtazapine is 20-40 hours and therefore the drug is suitable for administration once a day. It is preferable to take the daily dose of the drug at one time, before bedtime. can also be administered twice a day by dividing the daily dose in half (morning and night).

Treatment with Mirtazapine Canon should, if possible, continue for 4-6 months until the symptoms disappear completely. After that, the treatment can be gradually canceled. The drug begins to take effect after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response in 2-4 weeks. In case of insufficient response to treatment, the dose can be increased to the maximum dose (45 mg). If there is no response to treatment after another 2-4 weeks, treatment should be discontinued.

Adults

Elderly

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

Patients with renal and hepatic impairment

Instructions for use
Mirtazapine tab p.o 30mg No. 30

Dosage forms
tablets 30mg

Synonyms
Caliksta
Remeron

Group
Antidepressants - Indiscriminate Neuronal Uptake Inhibitors

International non-proprietary name
Mirtazapine

Composition
Active ingredient: mirtazapine 30 mg, in the form of mirtazapine hemihydrate 31 mg.

Manufacturers
Canonpharm production (Russia)

pharmachologic effect
Mirtazapine is a tetracyclic antidepressant with a predominantly sedative effect. The drug is most effective in depressive conditions with the presence in the clinical picture of symptoms such as inability to experience pleasure and joy, loss of interest (anhedonia), psychomotor retardation, sleep disturbances (especially in the form of early awakenings) and weight loss, as well as other symptoms: suicidal thoughts and diurnal mood swings. The antidepressant effect of the drug usually occurs after 1-2 weeks of treatment. Pharmacodynamics. Mirtazapine is an antagonist of presynaptic alpha2-adrenergic receptors in the central nervous system and enhances the 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, the S (+) enantiomer - blocking alpha2- and 5-HT2 receptors, and R (-) - the enantiomer - blocking 5-HT3 receptors. The sedative properties of mirtazapine are due to its antagonistic activity towards H1-histamine receptors. Mirtazapine is generally well tolerated. It has practically no m-anticholinergic activity and, in therapeutic doses, has a limited effect on the cardiovascular system (for example, orthostatic hypotension). Pharmacokinetics. Suction. After oral administration of the drug, mirtazapine is rapidly absorbed (bioavailability about 50%), reaching a maximum concentration in blood plasma after about 2 hours. Distribution. About 85% of mirtazapine binds to plasma proteins. A stable concentration of the substance is achieved in 3-4 days and does not change in the future. In the recommended dose range, the pharmacokinetic parameters of mirtazapine have a linear dependence on the administered dose of the drug. Metabolism. Mirtazapine is extensively metabolized. The main pathways of its metabolism in the body are demethylation and oxidation followed by conjugation. Cytochrome P450-dependent isoenzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite mirtazapine, while the CYP3A4 isoenzyme presumably determines the formation of N-demethylated and N-oxidized metabolites. De-methylmirtazapine is pharmacologically active and appears to be pharmacokinetically similar to the parent compound. Excretion. Mirtazapine is excreted by the kidneys and through the intestines over several days. The average elimination half-life is 20 to 40 hours (rarely up to 65 hours). A shorter half-life is observed in young people. The clearance of mirtazapine is reduced in renal or hepatic insufficiency.

Side effect
Patients with depression have a range of disease-related symptoms, so it can sometimes be difficult to distinguish between disease-related symptoms and drug-related symptoms. Disorders of the blood and lymphatic system. Frequency not established: inhibition of hematopoiesis (granulocytopenia, agranulocytosis, aplastic anemia and thrombocytopenia), eosinophilia. Endocrine system disorders. Frequency not known: impaired secretion of antidiuretic hormone. Metabolic and nutritional disorders. Very often: increased appetite and weight gain; frequency not known: hyponatremia. Nervous system disorders. Very often: drowsiness (can lead to impaired concentration) is more common in the first weeks of treatment (dose reduction usually does not lead to a decrease in the sedative effect, but can reduce the effectiveness of the antidepressant), sedation, headache. Often: lethargy, dizziness, tremors; infrequently; paresthesias, restless legs syndrome, fainting; rarely: myoclonus; frequency not known: convulsions, serotonin syndrome, paresthesia of the oral mucosa, articulation disorder. Mental disorders. Often: unusual dreams, confusion, anxiety, insomnia; infrequently: nightmares, mania, agitation, hallucinations, psychomotor agitation (including akathisia, hyperkinesia); rarely: aggressiveness; frequency not known: suicidal thoughts, suicidal behavior. Vascular disorders. Often: orthostatic hypotension; infrequently: lowering blood pressure. Disorders from the gastrointestinal tract. Very common: dry mouth; often: nausea, vomiting, diarrhea; infrequently: hypoesthesia of the oral mucosa; frequency not known: swelling of the oral mucosa, increased salivation. Liver and biliary tract disorders. Rarely: increased activity of "liver" enzymes. Skin and subcutaneous tissue disorders Often: skin rash; frequency not known: Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, toxic epidermal necrolysis. Musculoskeletal and connective tissue disorders. Often: back pain, arthralgia, myalgia. General disorders and disorders together introduction. Often: local edema; infrequently: fatigue; frequency not known: generalized or localized edema. Usually, with antidepressant treatment, anxiety and insomnia (which can be symptoms of depression) may develop or worsen. Development or worsening of anxiety has been reported very rarely during treatment with mirtazapine. When evaluating the data obtained in the course of clinical studies, there was a temporary increase in the level of transaminases and gamma-glutamyl transpeptidase (however, there were no reported adverse reactions associated with taking mirtazapine, which occurred with a greater frequency than with placebo). In addition, the following adverse reactions may occur: withdrawal syndrome, urticaria, thirst.

Indications for use
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 up to 18 years (efficacy and safety have not been established); simultaneous reception with monoamine oxidase inhibitors (MAO).

Method of administration and dosage
The tablets should be taken orally, without chewing, with a little water. Food intake does not affect the pharmacokinetics of the drug. The half-life of mirtazapine is 20-40 hours and therefore the drug is suitable for administration once a day. It is preferable to take the daily dose of the drug at one time, before bedtime. Mirtazapine can also be administered twice a day by dividing the daily dose in half (morning and night). Treatment with the drug should, if possible, continue for 4-6 months until the symptoms disappear completely. After that, the treatment can be gradually canceled. The drug begins to take effect after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response in 2-4 weeks. In case of insufficient response to treatment, the dose can be increased to the maximum dose (45 mg). If there is no response to treatment after another 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, up 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, the dose should be increased under the direct supervision of a physician. Patients with renal and hepatic impairment. In patients with renal or hepatic impairment, the clearance of mirtazapine may be reduced. This should be taken into account when prescribing a drug for this category of patients.

Overdose
Toxicity studies indicate the absence of a clinically significant cardiotoxic effect in case of drug overdose. Symptoms: Central nervous system depression, accompanied by disorientation and prolonged sedation, hallucinations, tachycardia, moderate increase or decrease in blood pressure. There is a likelihood of more severe violations of the physiological functions of the body, which can lead to fatal outcomes at doses much higher than the therapeutic dose, especially with mixed overdoses. Treatment: In case of overdose, symptomatic therapy should be carried out, aimed at maintaining the vital functions of the body. It is recommended to take activated charcoal, gastric lavage.

Interaction
Pharmacokietic interaction Mirtazapine is extensively metabolized with the participation of CYP2D6 and CYP3A4 isoenzymes, and to a lesser extent with the participation of the CYP1A2 isoenzyme. The 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 at equilibrium. The use of mirtazapine in combination with a potent inhibitor of the CYP3A4 isoenzyme, 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 the CYP3A4 isoenzyme, such as HIV protease inhibitors. azole antifungal drugs, erythromycin, or nefazodop. Carbamazepine and phenytoin, inducers of the nzoenzyme CYP3A4, approximately doubled the clearance of mirtazapine, which led to a 45-60% decrease in plasma concentrations of mirtazapine. When adding carbamazepip or another inducer of hepatic metabolism (for example, rifampicin) to mirtazapine therapy, the dose of mirtazapine may need to be increased. When treatment with such a drug is discontinued, it may be necessary to reduce the dose of mirtazapine. When using the drug in combination with cimetidine, the bioavailability of mirtazapine may increase by more than 50%. The dose of mirtazapine may need to be reduced at the start of treatment in combination with cimetidine or increased when cimetidine is discontinued. In in vivo studies, mirtazapine had no effect on the pharmacokinetics of risperidone or paroxetine (a substrate of the CYP2D6 isoenzyme), carbamazepine and phenytoin (a substrate of the CYP3A4 isoenzyme), 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 stopping treatment with MAO inhibitors. Treatment with MAO inhibitors should be started no earlier than 2 weeks after stopping treatment with mirtazapine. Mirtazapine can enhance the sedative properties of benzodiazepines and other sedatives (in particular, most antipsychotics, H1-histamine receptor antagonists, opioids). Mirtazapine may increase the depressant effect of alcohol on the central nervous system, therefore patients should be warned to avoid alcohol consumption. Concomitant use with other serotonergic drugs (for example, L-tryptophan, triptan, tramadol, linezolid, selective serotonin reuptake inhibitors, venlafaxine, lithium preparations, hypericum perforatum preparations) can lead to the development of serotonin syndrome. Mirtazapine 30 mg once daily caused a small but statistically significant increase in MHO (International Normalized Ratio) in patients treated with warfarin. A more pronounced effect with a higher dose of mirtazapine cannot be ruled out. It is recommended that MHO be monitored for warfarin plus mirtazapine.

special instructions
Carefully. Correction of the dosage regimen and regular medical supervision are necessary for the following categories of patients: in patients with epilepsy and organic brain lesions (against the background of drug therapy, in rare cases, the development of convulsive states is possible); in patients with hepatic or renal impairment; in patients with heart disease (conduction disturbances, angina pectoris, or recent myocardial infarction); in patients with cerebrovascular diseases (including a history of ischemic attacks); in patients with arterial hypotension and conditions predisposing to hypotension (including dehydration and hypovolemia); in patients with drug abuse, drug dependence, mania, hypomania. Like other antidepressants, mirtazapine should be used with caution in the following cases: urinary disorders, including prostatic hyperplasia; acute angle-closure glaucoma and increased intraocular pressure; diabetes; hyponatremia. Pregnancy and the period of breastfeeding. The safety of using mirtazapine during pregnancy has not been established, therefore, the drug should be prescribed during pregnancy only in cases where the benefit to the mother outweighs the potential risk to the fetus, treatment should be carried out under the supervision of a physician. The use of serotonin reuptake inhibitors during pregnancy, especially in the later stages, may increase the risk of developing prospective pulmonary hypertension in newborns. It is not known whether mirtazapine is excreted in breast milk; therefore, the use of the drug during breastfeeding is not recommended. Suicide / suicidal thoughts or clinical worsening of the course of the disease. In young people (under 24 years old) with depression and other mental disorders, antidepressants, compared with placebo, increase the risk of suicidal thoughts and suicidal behavior, therefore, when prescribing the drug, such patients should correlate the risk of suicide and the benefits 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 over 65 years of age, it decreased slightly. Any depressive disorder in itself increases the risk of suicide, therefore, during treatment, the patient should be monitored for violations or changes in behavior, as well as suicidal tendencies. Taking into account the possibility of suicide, especially at the beginning of treatment, the patient should be given the smallest number of tablets of the drug in order to reduce the risk of overdose. Depression of bone marrow functions. Bone marrow suppression, usually manifested as granulocytopenia or agranulocytosis, is rarely observed with mirtazapine, appears mostly after 4-6 weeks of treatment and is reversible after discontinuation of treatment. The doctor should carefully consider (and inform the patient) symptoms such as fever, sore throat, stomatitis, and other signs of flu-like syndrome. If such symptoms appear, treatment should be discontinued and a blood test done. Jaundice. If signs of jaundice appear, drug treatment should be interrupted. Conditions requiring medical supervision. The drug should be prescribed with caution, as well as regular and careful monitoring of patients under the following conditions: Epilepsy and organic brain lesions. Although clinical experience shows that epileptic seizures are rare, both with mirtazapine and other antidepressants, the drug should be used with caution in patients with a history of epileptic seizures. Liver failure. With oral administration of mirtazapine at a dose of 15 mg, the clearance of mirtazapine decreased by approximately 35% in patients with mild to moderate hepatic impairment compared with patients with normal liver function. The mean plasma concentration of mirtazapine increased by approximately 55%. Renal failure With 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%, respectively, according to compared with healthy patients. The mean plasma concentration of mirtazapine increased by 55% and 115%, respectively. In patients with mild renal insufficiency (creatinine clearance 40-80 ml / min), there were no significant differences compared with the control group. Heart diseases such as conduction disturbances, angina pectoris and recent myocardial infarction. In these cases, the usual precautions are necessary when prescribing the drug and concomitant therapy. Decrease in blood pressure. Diabetes. In patients with diabetes, antidepressants can affect blood glucose levels. Dose adjustment of insulin and / or dose of oral hypoglycemic drugs may be required. Close observation is recommended. As with the use of other antidepressants, the following conditions may occur with the use of the drug: Worsening of psychotic symptoms can occur with the use of antidepressants to treat patients with schizophrenia or other mental disorders. Paranoid ideas may intensify. The depressive phase of bipolar disorder during treatment can transform into a manic phase. Despite the fact that antidepressants are not addictive, based on post-marketing experience, it appears that abrupt withdrawal of therapy after prolonged use can cause withdrawal symptoms. Most withdrawal symptoms are mild and self-limiting. The most frequently reported “withdrawal” symptoms were: dizziness, nausea, headache and malaise, agitation, and anxiety. While these symptoms have been reported as “withdrawal” symptoms, it should be understood that these symptoms may be related to an underlying medical condition. It is recommended to stop treatment with the drug gradually. The drug should be prescribed with caution to patients with urinary disorders, incl. with prostatic hypertrophy, as well as in patients with acute angle-closure glaucoma and increased intraocular pressure (however, the negative effect of the drug is unlikely due to the fact that the anticholinergic activity of mirtazapine is very weak). Akathisia / psychomotor agitation. The use of antidepressants is associated with the development of akathisia, which is characterized by subjectively unpleasant or anxious arousal with increased motor activity. These symptoms are most likely to appear during the first few weeks of treatment. Increasing the dose in this case can have a negative impact on the patient's health. Hyponatremia. Extremely rare cases of hyponatremia have been described with mirtazapine. Patients at risk (elderly or patients taking drugs that can cause hyponatremia) should be prescribed 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, disorder of the autonomic nervous system with possible rapid fluctuations in vital signs of the functional state of the body, changes in mental state, including confusion, irritability and severe agitation, progressive disorder of consciousness and coma. Care should be taken and close clinical control should be exercised when these drugs are taken concomitantly with mirtazapine. If such symptoms appear, treatment with the drug should be discontinued and symptomatic treatment should be started. Based on post-marketing experience, it turned out that serotonin syndrome occurs very rarely in patients receiving ionotherapy with mirtazapine. Use in elderly patients. Elderly patients are usually more sensitive, especially with regard to side effects. In clinical studies, it was not noted that in elderly patients, side effects are more common than in other age groups, but they may be more pronounced, but the data are still limited. Patients are advised to avoid the use of alcohol during drug treatment. Caution should be exercised when prescribing benzodiazepines at the same time as mirtazapine. Influence on the ability to drive vehicles and mechanisms. During treatment with the drug, one should avoid performing potentially hazardous activities that require a high speed of psychomotor reactions, such as driving vehicles or other mechanisms.

Storage conditions
Store in a dry, dark place, out of reach of children, at a temperature not exceeding 25 C.