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Pharmacological properties

the active substance of the drug Mirtazapine sandoz - Mirtazapine - is an active central presynaptic antagonist of α2 receptors, which increases noradrenergic and serotonergic transmission to the central nervous system. increased serotonergic transmission occurs exclusively through 5-nt1 receptors, since Mirtazapine blocks 5-nt2 and 5-nt3 receptors. Both enantiomers of Mirtazapine are involved in this effect. s (+) - enantiomer blocks α2 and 5-nt2 receptors, and r (-) - enantiomer blocks 5-nt3 receptors. in addition, Mirtazapine blocks H1 receptors, which determines its sedative properties. in therapeutic doses, practically does not show anticholinergic activity and does not affect the cardiovascular system.

Pharmacokinetics After oral administration, Mirtazapine is rapidly and well absorbed (bioavailability is about 50%), reaching Cmax in plasma after about 2 hours. Almost 85% of Mirtazapine binds to plasma proteins. Medium T½ - 20-40 hours; cases when T½ was 65 hours; shorter T½ usually observed in young patients. Longer T½ allows you to take the drug 1 time per day. Stable concentration is achieved after 3-4 days, after which the accumulation passes. Within the recommended dose, the pharmacokinetic parameters of Mirtazapine are linearly dependent on the dose taken. Eating does not affect the pharmacokinetics of Mirtazapine.

Mirtazapine is actively metabolized and excreted in the urine and feces for several days. The main ways of biotransformation are demethylation and oxidation with further conjugation. In vitro data (liver microsomes) indicate that the cytochrome P450 enzymes CYP 2D6 and CYP 1A2 are involved in the formation of Mirtazapine 8-hydroxymetabolite, while CYP 3A4 forms N-dimethyl and N-oxide metabolites. N-dimethyl metabolite is pharmacologically active and exhibits a similar pharmacological effect as the starting substance.

Mirtazapine clearance may decrease with renal or liver failure.

Indications

Treatment of deep depression.

Application

Adults an effective daily dose is usually 15–45 mg; the initial dose is 15 or 30 mg. if the initial dose is 15 mg, and the daily dose is 15 or 45 mg, appropriate dosage tablets are used. Mirtazapine begins to show effect after 1–2 weeks of treatment. adequate dose therapy should cause a positive response for 2–4 weeks. with insufficient reaction, the dose can be increased. if during the next 2–4 weeks the necessary effect is not revealed, the drug should be discontinued.

Elderly patients. The recommended dose is similar for adults. In order to achieve a satisfactory and safe result, increasing the dose for elderly patients is carried out under the strict supervision of a doctor.

Renal failure. Mirtazapine clearance may be reduced in patients with moderate or severe renal failure (creatinine clearance 40 ml / min). When prescribing Mirtazapine Sandoz in this category of patients, creatinine clearance should be monitored.

Liver failure. Mirtazapine clearance may decrease in patients with liver failure. This fact must be taken into account when prescribing Mirtazapine Sandoz in this category of patients, especially with severe liver failure. Mirtazapine Sandoz is prescribed, starting with the minimum dose and controlling the clearance of Mirtazapine, especially in case of increasing the dose.

T½ Mirtazapine is 20–40 hours, so it can be used once a day.

It is advisable to use the drug at one time, at night before bedtime. The daily dose of the drug can be divided into 2 doses (morning and evening; most of the dose should be taken at night).

Tablets should be used orally, swallow without chewing; if necessary, wash down with water.

Patients with depression are treated for a long period, at least 6 months, until the symptoms disappear completely.

It is recommended to discontinue treatment with Mirtazapine gradually, in order to avoid withdrawal symptoms.

Contraindications

Hypersensitivity to Mirtazapine or to any component of the drug. concomitant use of Mirtazapine with MAO inhibitors.

Side effects

In patients with depression, symptoms were identified that may be associated with the disease itself. however, it is sometimes difficult to determine which symptoms are a manifestation of the disease and which are the result of treatment with Mirtazapine.

The most common adverse reactions that occur in more than 5% of patients treated with Mirtazapine are drowsiness, sedation, dry mouth, weight gain, increased appetite, dizziness, and increased fatigue.

Side effects are classified according to the frequency of manifestations: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1 / 1000), the frequency is unknown (adverse reactions from spontaneous reports).

On the part of the blood and lymphatic system: the frequency is unknown - inhibition of bone marrow activity (granulocytopenia, agranulocytosis, aplastic anemia, thrombocytopenia), eosinophilia.

Metabolism and malnutrition: very often - weight gain, increased appetite; frequency unknown - hyponatremia.

Mental disorders: often - sleep disturbance, confusion, anxiety, insomnia; sometimes - nightmares, mania, agitation, hallucinations, psychomotor agitation (including akathisia, hyperkinesia); frequency unknown - suicidal thoughts, behavior.

From the side of the central nervous system: very often - drowsiness, sedation, headache; often - lethargy, dizziness, tremor; sometimes - paresthesia, increased fatigue of the legs, syncope; rarely - myoclonus; frequency unknown - convulsions (hemorrhages), serotonin syndrome, paresthesia of the oral mucosa.

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

From the digestive tract: very often - dry mouth; often - nausea, diarrhea, vomiting; sometimes - hypesthesia of the oral mucosa; frequency unknown - swelling of the oral mucosa.

From the hepatobiliary system: rarely - increased activity of transaminases in the blood serum.

On the part of the skin and subcutaneous tissue: often - exanthema; frequency unknown - Stevens-Johnson syndrome; bullous dermatitis; erythema multiforme; toxic epidermal necrolysis.

From the musculoskeletal system and connective tissue: often - arthralgia, myalgia, back pain.

From the endocrine system: frequency is unknown - impaired secretion of antidiuretic hormone.

General disorders: often - peripheral edema, increased fatigue.

It should be noted that dose reduction usually does not lead to a decrease in drowsiness / sedation, but may reduce the effectiveness of an antidepressant.

Agitation and insomnia, which may be symptoms of depression, may worsen as a result of treatment with antidepressants, including Mirtazapine.

Cases of suicidal thoughts and behavior were noted during Mirtazapine therapy or after treatment was discontinued.

A transient increase in transaminase and γ-glutamyl transferase levels was detected (however, no adverse reactions were reported).

special instructions

Suicide / suicidal thoughts or clinical impairment. depression is associated with an increased risk of suicidal thoughts, self-harm, suicide (cases associated with suicide). this risk is noted before severe remission occurs.since improvement may not occur during the first weeks or more of treatment, patients should be closely monitored by a physician until improvement occurs. according to general clinical experience, the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicidal attempts, or patients who show a pronounced degree of suicidal ideation before therapy, are known to have a high risk of suicidal thoughts or suicide attempts and must be closely monitored throughout treatment. Analysis of clinical trials of antidepressants that are used by adults with mental disorders indicates an increased risk of developing suicidal behavior when taking antidepressants compared with patients aged 25 years who received a placebo.

During antidepressant therapy, strict monitoring of patients with a high risk of suicidal behavior is necessary, especially at the beginning of therapy and after changing the dosage. Patients should be warned about the need to pay attention to any clinical manifestations, suicidal behavior or thoughts and unusual behavior changes, and seek medical advice immediately if such symptoms occur.

Taking into account the possibility of suicide, especially at the beginning of treatment, the patient must be given the minimum required number of tablets of the drug.

Inhibition of bone marrow activity. During treatment with Mirtazapine, bone marrow suppression was reported, which is usually manifested by granulocytopenia or agranulocytosis.

Some cases of agranulocytosis have been reported, they are usually reversible, but sometimes with lethal consequences (mainly in patients aged 65 years). The doctor should pay attention to symptoms such as fever, sore throat, stomatitis, or other signs of infection. When such symptoms occur, treatment should be discontinued and a blood test done.

Jaundice. Treatment should be stopped when jaundice occurs.

Conditions in which strict medical supervision is required. Careful dosing, as well as regular and careful monitoring, are necessary for patients with the following conditions:

  • epilepsy and organic brain damage. Mirtazapine should be used with extreme caution in patients with a history of epileptic seizures. Treatment should be discontinued in patients who develop epileptic seizures or when an increase in the frequency of epileptic seizures is noted;
  • liver failure: after oral administration of 15 mg of Mirtazapine, its clearance is reduced by approximately 35% in patients with mild to moderate hepatic insufficiency compared with patients with normal liver function. The average plasma concentration of Mirtazapine increases by approximately 55%. When prescribing 30 mg of Mirtazapine, the benefit / potential risk ratio for the patient should be considered;
  • renal failure: after a single oral administration of 15 mg of Mirtazapine to patients with moderate renal insufficiency (10 ml / min ≤ creatinine clearance 40 ml / min) or severe (creatinine clearance 10 ml / min), Mirtazapine clearance decreased by approximately 30 and 50%, respectively compared to healthy patients. The average plasma concentration of Mirtazapine increased by 55 and 115%, respectively. There were no significant differences in patients with mild renal failure (40 ml / min ≤ creatinine clearance of 80 ml / min) compared with the control group. When prescribing 30 mg of Mirtazapine, the benefit / potential risk ratio for the patient should be considered and creatinine clearance controlled;
  • heart disease, such as conduction disorder, angina pectoris, and recent myocardial infarction. In these cases, concomitant therapy should be prescribed with caution;
  • arterial hypotension;
  • diabetes: in patients with diabetes, antidepressants can affect blood glucose levels. It may be necessary to adjust the dose of insulin and / or oral hypoglycemic drugs and careful monitoring is recommended.

As with other antidepressants, the following should be considered:

  • when using antidepressants in patients with schizophrenia or other mental disorders, psychotic symptoms may worsen; paranoid thoughts may become more intense;
  • in the treatment of the depressive phase of bipolar disorder, it can go into the manic phase. Patients with a history of manic or hypomanic manifestations must be carefully monitored. The use of Mirtazapine should be discontinued if the patient enters the manic phase;
  • although addiction to the drug does not occur, post-marketing experience shows that the sudden cessation of treatment after prolonged use can sometimes lead to withdrawal symptoms. Most withdrawal reactions show minor clinical symptoms and go away on their own. Among the various withdrawal symptoms reported, the most common were dizziness, agitation, anxiety, headache, and nausea. Although they have been reported as withdrawal symptoms, it should be remembered that they may be related to the progress of the underlying disease. It is recommended to gradually discontinue treatment with Mirtazapine;
  • caution is necessary in the treatment of patients with urinary disorders, including as a consequence of prostatic hypertrophy, patients with acute angle-closure glaucoma and increased intraocular pressure (however, the effect of the drug Mirtazapine Sandoz is unlikely due to its very low anticholinergic activity);
  • akathisia / psychomotor agitation: the use of antidepressants is associated with the development of akathisia, which was characterized by subjectively unpleasant or anxious agitation and the need to often move along with the inability to sit or stand still. Most likely, these symptoms can occur during the first few weeks of treatment, so increasing the dose can be harmful.

Hyponatremia. There were separate reports of hyponatremia when using Mirtazapine, which is associated with inadequate secretion of antidiuretic hormone. Elderly patients or those using concomitant therapy that can cause hyponatremia require special monitoring.

Serotonin syndrome. Interaction with serotonergic active substances: serotonin syndrome can occur when selective serotonin reuptake inhibitors are used in combination with other serotonergic active substances. Symptoms of serotonin syndrome can be hyperthermia, muscle stiffness, myoclonus, autonomous instability with possible rapid fluctuations in vital signs. Changes in mental state include confusion, irritation, and high arousal, which progresses to delirium and coma. Serotonin syndrome occurs very rarely in patients who receive Mirtazapine alone.

Elderly patients. When prescribing Mirtazapine to elderly patients, one should be aware of the undesirable effects that occur with the use of antidepressants. The occurrence of adverse reactions in the elderly was noted no more often than in patients of other age categories.

Lactose.The drug contains lactose, so it should not be prescribed to patients with the rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy and lactation. The safety and effectiveness of Mirtazapine during pregnancy have not been established, therefore, the drug should not be prescribed to pregnant women. It is not known whether Mirtazapine passes into breast milk; therefore, breast-feeding should be discontinued during treatment.

Children. The drug is not used to treat children. Suicidal behavior (suicide attempts and suicidal thoughts), hostility (mainly aggression, opposition behavior and anger) were most often detected among children and adolescents who were treated with antidepressants. If, based on clinical need, a decision was made on antidepressant therapy, the patient must be carefully monitored in connection with the possible occurrence of suicidal symptoms. In addition, there are no data on the safety of use in children and adolescents during the period of growth, maturation, cognitive and behavioral development.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The drug affects the ability to drive vehicles and work with other mechanisms - concentration may worsen (especially at the initial stage of treatment). Patients using Mirtazapine Sandoz should avoid performing potentially hazardous activities that require attention.

Interactions

Pharmacodynamic interactions

Mirtazapine should not be taken concomitantly with MAO inhibitors or for 2 weeks after the end of therapy. After completion of treatment with Mirtazapine, it should take about 2 weeks before patients can use MAO inhibitors.

In addition, the simultaneous administration of Mirtazapine with selective serotonin reuptake inhibitors and other serotonergic active substances (L-tryptophan, triptan, tramadol, linezolid, venlafaxine, lithium, and St. Johns wort preparations (Hypericum perforatum)) can lead to serotonin-induced effects. In the combined use of these active substances with Mirtazapine, caution is advised and under strict medical supervision.

Mirtazapine may enhance the sedative properties of benzodiazepines and other sedatives (in particular, most antipsychotics, H antagonists1receptors, opioids).

Mirtazapine Sandoz can enhance the depressive effect of alcohol on the central nervous system, so patients should refrain from drinking alcohol during the period of treatment with the drug.

Mirtazapine at a dose of 30 mg once a day causes a small, but statistically significant increase in the international normalized index in patients treated with warfarin. It is recommended to control it in case of concomitant use of warfarin with Mirtazapine in connection with its possible increase.

Pharmacokinetic interactions

Carbamazepine and phenytoin, CYP 3A4 inducers increase the clearance of Mirtazapine by approximately 2 times and, as a result, the average concentration of Mirtazapine in blood plasma decreases by 60 and 45%, respectively. When carbamazepine or any other inducer of hepatic metabolism (e.g. rifampicin) is added to Mirtazapine therapy, the dose of the latter should be increased. If treatment with such a drug is discontinued, it may be necessary to reduce the dose of Mirtazapine.

Concomitant use of potent CYP 3A4 ketoconazole inhibitor increased Cmax in plasma and AUC of Mirtazapine approximately 40 and 50%, respectively.

When using cimetidine (a weak inhibitor of CYP 1A2, CYP 2D6 and CYP 3A4) with Mirtazapine, the average plasma concentrations of Mirtazapine can increase by more than 50%. The dose should be reduced with the combined use of Mirtazapine with potent CYP 3A4 inhibitors, HIV protease inhibitors, azole antifungal agents, erythromycin, cimetidine or nefazodone.

No clinically significant pharmacokinetic interaction was found with the simultaneous use of Mirtazapine with paroxetine, amitriptyline, risperidone or lithium.

Overdose

Experience with an overdose of Mirtazapine suggests that mild symptoms were noted. CNS depression with disorientation and prolonged sedation was reported, which was accompanied by tachycardia and minor arterial hypo- or hypertension. however, more serious consequences (including fatal) are possible when used in a dose much higher than the therapeutic, especially with mixed overdoses.

In case of an overdose, patients should undergo appropriate symptomatic therapy and maintain vital functions of the body. You can use activated charcoal or gastric lavage.

Storage conditions

It does not require special storage conditions.