Calixta (Mirtazapine)

Active substance:

Excipients:

lactose monohydrate - 44.4 mg,

corn starch - 28 mg,

hyprolose - 15 mg,

microcrystalline cellulose - 15 mg,

pregelatinized starch - 15 mg,

talc - 1.4 mg,

magnesium stearate - 0.7 mg,

silicon dioxide - 0.5 mg.

Shell composition:

hypromellose-5 CPS - 2.4 mg, macrogol 6000 - 0.2 mg, titanium dioxide - 0.25 mg, iron dye yellow oxide (E172) - 0.1 mg, talc - 0.05 mg.

Myrtazapine is an antagonist of presynaptic α2-adrenergic receptors in the CNS and enhances central noreprenergic and serotonergic transmission of nerve impulses. At the same time, the strengthening of serotonergic transmission is realized only through serotonin 5-HT1 receptors, since myrtazapine blocks serotonin 5-HT2- and 5-HT3 receptors. It is believed that both enantiomers of Mirtazapine have antidepressive activity, S(+) enantiomer - blocking α2-adreno- and serotonin 5-HT2 receptors, aR(-) enantiomer - blocking serotonin 5-HT3-receptors.

The sedative properties of Mirtazapine are due to its antagonistic activity in relation to H1-histamine receptors.

Mirtazapin is usually well tolerated. In therapeutic doses - practically does not have a m-choline blocking effect and practically does not affect the cardiovascular system.

Pharmacokinetics

After oral administration, Mirtazapin is quickly absorbed (bioavailability about 50%), reaching Cmax in blood plasma after about 2 hours. About 85% of Myrtazapine binds to plasma proteins. The average T1/2 is from 20 to 40 hours (rarely up to 65 hours). Shorter T1/2 is observed in young people. The equilibrium concentration of the substance is reached in 3-4 days and does not change in the future.

In the recommended dose range, the pharmacokinetic indicators of Mirtazapin have a linear dependence on the administered dose of the drug. Eating does not affect the pharmacokinetics of the drug. Myrtazapine is actively metabolized and excreted with urine and feces for several days. The main ways of its metabolism in the body are demethylation and oxidation followed by conjugation. Cytochrome P450 isoenzymes (CYP2D6 and CYP1A2) are involved in the formation of 8-hydroxymethabolite Mirtazapine, while CYP3A4 presumably determines the formation of N-demethylated and N-oxidized metabolites.

Demetylmirtazapine is pharmacologically active.

Mirtazapine clearance decreases in renal or liver failure.

Depression.

The safety of using Calixta during pregnancy in humans has not been established, but no teratogenic effect has been detected in animals, so the drug can be used during pregnancy only when the benefit to the mother exceeds the potential risk to the fetus.

The use of Calixta during lactation is not recommended due to the lack of data on its excretion with breast milk in humans.

- patients with such rare hereditary problems as lactose intolerance, lactase deficiency or glucose-galactose malabsorption should not be prescribed;

- hypersensitivity to myrtazapine or any of the auxiliary substances;

- since the safety and effectiveness of Calixta for childhood have not been established, it is not recommended to use Calixta for the treatment of children under 18 years of age.

With caution:

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

- acute closed-angle glaucoma and increased intraocular pressure;

- diabetes mellitus;

- impaired urination, including prostate hyperplasia;

- with simultaneous use of benzodiazepines with Calixta. 

Dosage correction and regular medical control are necessary for the following categories of patients:

- patients with epilepsy and organic brain lesions (against the background of therapy with Calixta, seizures may rarely develop);

- patients with liver or kidney failure;

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

- patients with cerebrovascular diseases (including those with ischemic stroke in the history);

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

- patients who abuse medicines, with dependence on drugs affecting the CNS, with mania, hypomania.

From the gastrointestinal tract: very often - dry mouth; often - nausea, diarrhea, vomiting; infrequently - decreased sensitivity of the oral mucosa; frequency is not established - swelling of the oral mucosa.

From the blood and lymphatic system: frequency is not established - bone marrow oppression (granulocytopenia, agranulocytosis, aplastic anemia and thrombocytopenia), eosinophilia.

On the part of the nervous system: very often - drowsiness (which can lead to impaired concentration), usually occurring during the first weeks of treatment. (N.B. reducing the dose usually does not lead to less sedative effect, but can reduce the effectiveness of the antidepressant), sedation, headache; often - lethargy, dizziness, tremors; infrequently - paresthesia, restless leg syndrome, fainting; rarely - myoclon

From the skin and subcutaneous tissue side: often - skin rash.

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

From the endocrine system side: frequency is not established - violation of the secretion of the antidiuretic hormone.

From the metabolic and nutrition side: very often - increased appetite.

From the cardiovascular system: often - orthostatic hypotension; infrequently - decreased blood pressure.

General disorders and disorders at the place of administration: often - local swelling; infrequently - fatigue.

From the liver and biliary tract: rarely - increased serum transaminase activity.

Mental disorders: often - unusual dreams, confusion, anxiety*, insomnia*, infrequently - nightmares, mania, agitation, hallucinations, psychomotor arousal (including acatasia and hyperkinesia); frequency is not established - suicidal ideas, suicidal behavior. * usually, anxiety and in

When treated with Calixta, the development or deterioration of anxiety and insomnia was very rarely reported.

Pharmacodynamic interaction

Myrtazapine should not be used in combination with MAO inhibitors or within two weeks after termination of treatment with an MAO inhibitor.

Myrtazapine can enhance the sedative properties of benzodiazepines and other sedatives. Care should be taken when prescribing these drugs together with myrtazapine.

Mirtazapin can increase the depressive effect of alcohol on the CNS. Therefore, patients should be warned about the need to avoid drinking alcohol.

In the case of other serotonergic drugs (e.g. selective serotonin and venlafaxin capture inhibitors) in combination with myrtazapine, there is a risk of interaction that can lead to the development of serotonin syndrome.

Myrtazapine at a dose of 30 mg 1 time/day caused a small but statistically reliable increase in MHO (international normalized ratio) in subjects treated with warfarin. A more pronounced effect cannot be excluded at a higher dose of myrtazapine. It is recommended to control MHO in case of warfarin treatment in combination with myrtazapine.

Myrtazapine is intensively metabolized with the participation of CYP2D6 and CYP3A4 isoenzymes, and to a lesser extent with the participation of the CYP1A2 isoenzyme. A study of interaction in healthy volunteers showed that paroxetine, an inhibitor of the CYP2D6 isoenzyme, does not affect the pharmacokinetics of myrtazapine in an equilibrium state. Introduction combined with a powerful CYP3A4 isoenzyme inhibitor, ketoconazole increased the maximum concentration in plasma and AUC myrtazapine by about 40% and 50%, respectively.

Care should be taken when using myrtazapine in combination with powerful inhibitors of the isoenzyme CYP3A4, HIV protease inhibitors, azolic antifungal drugs, erythromycin or nefazodon. Carbamazepine and phenytoin, inductors of the isoenzyme CYP3A4, increased myrtazapine clearance by about half, which led to a 45-60% decrease in myrtazapine concentrations in plasma.

If carbamazepine or other inductor of microsomal liver enzymes (e.g. rifampicin) to myrtazapine therapy, the dose of myrtazapine should be increased if necessary.

If you stop treatment with such a drug, it may be necessary to reduce the dose of myrtazapine. When using myrtazapine in combination with cimetidine, the bioavailability of myrtazapine can increase by more than 50%. The dose of myrtazapine, if necessary, should be reduced at the beginning of treatment in combination with cimetidine or increased when cymetidine treatment is discontinued.

In in vivo interaction studies, myrtazapine did not affect the pharmacokinetics of risperidone or paroxetine (substrate of the isoenzyme CYP2D6), carbamazepine (substrate of the isoenzyme CYP3A4), amitriptylin, There were no important clinical effects or changes in pharmacokinetics in humans in the treatment with myrtazapine in combination with lithium.

Tablets should be taken orally, washed down with liquid if necessary, and swallowed without chewing.

Adults:

The effective daily dose is usually between 15 mg and 45 mg; the initial dose is 15 mg or 30 mg.

Elderly patients:

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 increase should be carried out under the direct supervision of a doctor.

Liver and kidney dysfunction:

In patients with renal or liver failure, myrtazapine clearance may be reduced. This should be taken into account when prescribing Calixta in this category of patients.

Calixta can be taken once/day, preferably at the same time, before bedtime. Calixta can also be prescribed for administration 2 times/day, diluting the daily dose in half (once in the morning and once at night, a higher dose should be taken at night).

Treatment should, if possible, continue for 4-6 months until the symptoms disappear completely in the patient. After that, treatment can be gradually canceled. Mirtazapin usually begins to have its effect after 1-2 weeks of treatment. Treatment with an adequate dose should lead to a positive result in 2-4 weeks. If necessary, the dose can be increased to the maximum dose (up to 45 mg). In the absence of positive dynamics of treatment, treatment should be discontinued after another 2-4 weeks.

In case of an overdose, symptomatic therapy should be carried out to maintain vital functions of the body.

You should enter activated carbon or rinse your stomach. Experience with an overdose of Calixta only indicates that symptoms are usually mild. CNS oppression was reported, accompanied by disorientation and prolonged sedative effect combined with tachycardia and a slight increase or decrease in blood pressure.

However, there is a possibility of more severe results (including death) at doses far exceeding the therapeutic dose, especially when overdoses with several drugs taken simultaneously.

When using Calixta, keep in mind:

- Deterioration of psychotic symptoms may occur when using antidepressants to treat patients with schizophrenia or other psychotic disorders; paranoid ideas may increase.

- The depressive phase of manic-depressive psychosis against the background of treatment can be transformed into a manic phase.

- In young people (under 24 years of age) with depression and other mental disorders, antidepressants, compared to placebo, increase the risk of suicidal thoughts and suicidal behavior. Therefore, when prescribing Calixta in young people (under 24 years of age), the risk of suicide and the benefits of using the drug should be correlated. In short-term studies, the risk of suicide in people over 24 years of age did not increase, and in people over 65 years of age - slightly decreased. Any depressive disorder itself increases the risk of suicide. Therefore, during treatment, the patient should be monitored to identify disorders or behavioral changes, as well as suicidal tendencies.

- Despite the fact that Calixta is not addictive, based on their post-registration experience, it turned out that a sharp termination of treatment after prolonged use can sometimes cause withdrawal symptoms. Most withdrawal reactions are weak and self-restricting. The following symptoms of cancellation were most often reported: dizziness, agitation, anxiety, headache and nausea. Although they were reported as symptoms of withdrawal, it should be understood that these symptoms may be related to the underlying disease. It is recommended to stop treatment with myrtazapine gradually.

- Elderly patients are usually more sensitive, especially with side effects. Clinical studies of Calixta did not indicate that side effects are more common in elderly patients than in other age groups, but they may be more pronounced, but the data are still limited.

- If there are signs of jaundice, treatment should be stopped.

- Patients are advised to avoid using alcohol in the treatment with Calixta.

- Bone marrow depression, usually appearing in the form of granulocytopenia or agranulocytosis, is rarely observed when using Calixta. Appears mostly after 4-6 weeks of treatment and is reversible after discontinuation of treatment. The doctor should pay attention to symptoms such as fever, sore throat, stomatitis, and other signs of influenza-like syndrome and inform the patient about it; if such symptoms appear, treatment should be discontinued and a blood test.

Impact on the ability to drive vehicles and mechanisms

Calixta can reduce concentration. In the process of antidepressant treatment, patients should avoid performing potentially dangerous activities that require high speed psychomotor reactions, such as driving a car or driving mechanisms.

Yellow film-coated tablets, oblong, with risk on one side.