Universal reference book for medicines
Name of the preparation: KALIKSTA ® (CALIXTA)

Active substance: mirtazapine

Type: Antidepressant

Manufacturer: BELUPO, Pharmaceuticals & Cosmetics (Croatia)
Composition, form of production and packaging
The tablets covered with a film cover of
yellow color, oblong, with risk on one side.

1 tab.

mirtazapine 15 mg

Auxiliary substances: lactose monohydrate - 44.4 mg, corn starch - 28 mg, giprolose - 15 mg, microcrystalline cellulose - 15 mg, pregelatinized starch - 15 mg, talc - 1.4 mg, magnesium stearate - 0.7 mg, silicon dioxide - 0.5 mg.

The composition of the membrane: hypromellose-5 CPS - 2.4 mg, macrogol 6000 - 0.2 mg, titanium dioxide - 0.25 mg, iron-oxide oxide yellow (E172) 0.1 mg, talc-0.05 mg.

30 pcs.
- blisters (1) - packs of cardboard.
The tablets covered with a film membrane are brownish-pink in color, oblong, with a risk on one side.

1 tab.

mirtazapine 30 mg

Excipients: lactose monohydrate - 88.8 mg, corn starch - 56 mg, giprolose - 30 mg, microcrystalline cellulose - 30 mg, pregelatinized starch - 30 mg, talc - 2.8 mg, magnesium stearate 1.4 mg, silicon dioxide - 1 mg.

The composition of the membrane: hypromellose-5 CPS - 4.8 mg, macrogol 6000 - 0.4 mg, titanium dioxide - 0.5 mg, iron oxide oxide yellow (E172) - 0.15 mg, iron oxide red oxide (E172) - 0.05 mg, talc 0.1 mg.

15 pcs.
- blisters (2) - packs of cardboard.
The tablets covered with a film membrane of white color, oblong.

1 tab.

mirtazapine 45 mg

Auxiliary substances: lactose monohydrate - 133.2 mg, corn starch - 84 mg, giprolose - 45 mg, microcrystalline cellulose - 45 ml, pregelatinized starch 45 mg, talc 4.2 mg, magnesium stearate 2.1 mg, silicon dioxide 1.5 mg.

The composition of the membrane: hypromellose-5 CPS - 7.2 mg, macrogol 6000 - 0.6 mg, titanium dioxide - 1.05 mg, talc - 0.15 mg.

15 pcs.
- blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2013.

PHARMACHOLOGIC EFFECT

Mirtazapine is a presynaptic antagonist?
2- adrenoreceptors in the central nervous system and enhances the central noradrenergic and serotonergic transmission of nerve impulses. In this case, the increase in serotonergic transmission is realized only through serotonin 5-HT 1 -receptors, since mirtazapine blocks serotonin 5-HT 2 - and 5-HT 3 -receptors. It is believed that both enantiomers of mirtazapine have antidepressant activity, S (+) enantiomer - blocking? 2- adreno-and serotonin 5-HT 2 -receptors, aR (-) enantiomer - blocking serotonin 5-HT 3 -receptors.
Sedative properties of mirtazapine are due to its antagonistic activity against H 1 -histamine receptors.

Mirtazapine is usually well tolerated.
In therapeutic doses, it practically has no m-cholin blocking effect and practically does not affect the cardiovascular system.
PHARMACOKINETICS

After oral administration of the drug, mirtazapine is rapidly absorbed (bioavailability is about 50%), reaching Cmax in the blood plasma after about 2 hours. About 85% of mirtazapine binds to plasma proteins.
The average T 1/2 is between 20 and 40 hours (rarely up to 65 hours). A shorter T 1/2 is observed in young people. The equilibrium concentration of the substance is reached 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. Eating does not affect the pharmacokinetics of the drug. Mirtazapine is actively metabolized and excreted in urine and feces for several days. The main ways of its metabolism in the body are demethylation and oxidation followed by conjugation.Isozymes of cytochrome P450 (CYP2D6 and CYP1A2) are involved in the formation of mirtazapine 8-hydroxymetabolide, while CYP3A4 presumably determines the formation of N-demethylated and N-oxidized metabolites. Demethylmirtazapine is pharmacologically active. The clearance of mirtazapine decreases with renal or hepatic insufficiency.
INDICATIONS

Depression.

DOSING MODE

Tablets should be taken orally, if necessary, washed down with liquid, 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, an increase in the dose should be made under the direct supervision of a physician.
Dysfunction of the liver and kidneys:

In patients with renal or hepatic insufficiency, the clearance of mirtazapine may be reduced.
This should be taken into account when appointing Kalikst in this category of patients.
Kalikst preparation can be taken 1 time / day, preferably at the same time, before bedtime.
Kalikst can also be prescribed for admission 2 times / day, dividing the daily dose in half (once in the morning and once a night, a higher dose should be taken at night).
Treatment should, if possible, continue for 4-6 months until the symptoms disappear completely.
After that, the treatment can be gradually canceled. Mirtazapine begins to act normally 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, after 2-4 weeks treatment should be discontinued.
SIDE EFFECT

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

To indicate the frequency of side effects, the following classification is used: very often (? 1/10), often (> 1/100 and? 1/10), infrequently (> 1/1000 and? 1/100), rarely (> 1/10000 and? 1/1000), the frequency is not set (? 1/10000)

On the part of the blood and lymphatic system: the frequency is not established - bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia and thrombocytopenia), eosinophilia.

From the nervous system: very often - drowsiness (which can lead to impaired concentration), usually occurring during the first weeks of treatment.
(NB reduction of the dose usually does not lead to less sedation, but may decrease the effectiveness of the antidepressant), sedation, headache; often - lethargy, dizziness, tremor;infrequently - paresthesia, restless legs syndrome, fainting; rarely - myoclonus, very rarely - seizures (stroke), serotonin syndrome, paresthesia of the oral mucosa.
From the digestive tract: very often - dry mouth;
often - nausea, diarrhea, vomiting; infrequent - a decrease in the sensitivity of the oral mucosa; frequency is not established - edema of the oral mucosa.
From the skin and subcutaneous tissues: often - skin rash.

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

On the part of the endocrine system: the frequency is not established - a violation of the secretion of antidiuretic hormone.

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

From the cardiovascular system: often - orthostatic hypotension;
infrequently - a decrease in blood pressure.
General disorders and disorders at the injection site: often - local edema;
infrequently - fatigue.
From the liver and biliary tract: rarely - increased activity of transaminases of the serum.

Mental disturbances: often - unusual dreams, confusion, anxiety *, insomnia *, infrequently - nightmares, mania, agitation, hallucinations, psychomotor agitation (including acacia and hyperkinesia);
frequency not established - suicidal ideation, suicidal behavior.
* usually with the treatment of antidepressants, anxiety and insomnia, which may be symptoms of depression, may develop or worsen.
When treating with Kalikst, the development or worsening of anxiety and insomnia was reported very rarely.
CONTRAINDICATIONS

- hypersensitivity to mirtazapine or to any of the excipients;

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

- Since the safety and efficacy of Kalikst for children are not established, it is not recommended to apply Kalikst to children under 18 years of age.

Carefully

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

- patients with epilepsy and organic lesions of the brain (on the background of therapy with Kalikst preparation, in rare cases, convulsions may develop);

- patients with hepatic or renal insufficiency;

- Patients with heart diseases (conduction disorders, angina pectoris or recent myocardial infarction);

- Patients with cerebrovascular diseases (including with an ischemic stroke in the anamnesis);

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

- patients who abuse drugs, with dependence on drugs that affect the central nervous system, with mania, hypomania.

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

- violation of urination, incl.
with hyperplasia of the prostate;
- acute angle-closure glaucoma and increased intraocular pressure;

- diabetes;

- with simultaneous use of benzodiazepines with Kalikst preparation.

PREGNANCY AND LACTATION

The safety of Kalikst during pregnancy in humans has not been established, however, there is no teratogenic effect in animals, so the drug can be used during pregnancy only if the benefit to the mother exceeds the potential risk to the fetus.

The use of Kalikst during lactation is not recommended because of the lack of data on its excretion in human milk.

APPLICATION FOR FUNCTIONS OF THE LIVER

Use with caution in patients with renal insufficiency.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Use with caution in patients with hepatic insufficiency.

APPLICATION FOR CHILDREN

Since the safety and efficacy of Kalikst for children are not established, it is not recommended to apply Kalikst to children under 18 years of age.

APPLICATION IN ELDERLY PATIENTS

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.

SPECIAL INSTRUCTIONS

When using Kalikst, one should keep in mind:

- Deterioration of psychotic symptoms can occur with the use of antidepressants for the treatment of patients with schizophrenia or other psychotic disorders;
Paranoid ideas can intensify.
- The depressive phase of manic-depressive psychosis on the background of treatment can be transformed into a manic phase.

- 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.
Therefore, with the appointment of Kalikst in young people (younger than 24 years), the risk of suicide and the benefits of using the drug should be correlated. In short-term studies in people over 24 years of age, the risk of suicide did not increase, but in people older than 65 years, it declined slightly. Any depressive disorder in itself increases the risk of suicide. Therefore, during the treatment for the patient, surveillance should be established to detect abnormalities or changes in behavior, as well as suicidal tendencies.
- Despite the fact that Kalikst's preparation is not addictive, based on their post-registration experience, it turned out that a sharp cessation of treatment after prolonged use can sometimes cause withdrawal symptoms.
Most cancellation reactions are weak and self-limiting. The most commonly reported symptoms were: dizziness, agitation, anxiety, headache and nausea. Although they have been reported as symptoms of withdrawal, it should be understood that these symptoms can be associated with underlying disease. It is recommended to stop treatment with mirtazapine gradually.
- Elderly patients are usually more sensitive, especially with regard to side effects.
Clinical studies of Kalikst did not show that side effects occur more often in elderly patients than in other age groups, but they may be more pronounced, but the data are still limited.
- If symptoms of jaundice appear, treatment should be discontinued.

- Patients are advised to avoid the use of alcohol in the treatment of Kalikst.

- Oppression of bone marrow functions, usually appearing in the form of granulocytopenia or agranulocytosis, is rarely observed with the use of Kalikst preparation.Appears mostly after 4-6 weeks of treatment and reversibly after discontinuation of treatment.
The doctor should carefully consider such symptoms as fever, sore throat, stomatitis, and other signs of flu-like syndrome and inform the patient about it; when such symptoms appear, you must stop treatment and make a blood test.
Impact on the ability to manage vehicles and mechanisms

Kaliksta preparation can reduce concentration of attention.
In the process of treatment with antidepressants, patients should avoid performing potentially dangerous activities requiring high rates of psychomotor reactions, such as driving a car or controlling machinery.
OVERDOSE

The experience with an overdose of Kalikst alone indicates that the symptoms are usually mild.
Reported CNS depression, accompanied by disorientation and prolonged sedation in combination 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 overdosed with several drugs taken simultaneously.
In case of an overdose, symptomatic therapy should be used to maintain the vital functions of the body.
You should enter activated charcoal or rinse the stomach.
DRUG INTERACTION

Pharmacokinetic 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 interaction in healthy volunteers showed that paroxetine, an inhibitor of the isoenzyme CYP2D6, does not affect the pharmacokinetics of mirtazapine in the equilibrium state. Introduction in combination with a potent inhibitor of the isoenzyme CYP3A4, ketoconazole increased the maximum plasma concentration and AUC of mirtazapine by approximately 40% and 50%, respectively. Caution should be exercised when using mirtazapine in combination with potent inhibitors of the CYP3A4 isoenzyme, HIV protease inhibitors, azole
antifungal drugs, erythromycin or nefazodone.

Carbamazepine and phenytoin, inductors of the CYP3A4 isoenzyme, 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 other inducer of microsomal liver enzymes (eg rifampicin) to mirtazapine therapy, the dose of mirtazapine should be increased if necessary. When discontinuing treatment with such a drug, it may be necessary to reduce the dose of mirtazapine.
When mirtazapine is used in combination with cimetidine, the bioavailability of mirtazapine may increase by more than 50%.
The dose of mirtazapine, if necessary, should be reduced at the beginning of treatment in combination with cimetidine or increased when cimetidine is discontinued.
In studies on in vivo interactions, mirtazapine had no effect on the pharmacokinetics of risperidone or paroxetine (substrate of the isoenzyme CYP2D6), carbamazepine (substrate of the isoenzyme CYP3A4), amitriptyline, cimetidine or phenytoin.

There were no significant clinical effects or changes in pharmacokinetics in humans when treated with mirtazapine in combination with lithium.

Pharmacodynamic interaction

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

Mirtazapine can enhance the sedative properties of benzodiazepines and other sedatives.
Caution should be exercised when prescribing these medicines together with mirtazapine.
Mirtazapine can enhance the depressive effect of alcohol on the central nervous system.
Therefore, patients should be warned about the need to avoid drinking alcohol.
In the case of other serotonergic drugs (for example, selective inhibitors of serotonin and venlafaxine seizure) in combination with mirtazapine, there is a risk of interaction that may lead to the development of serotonin syndrome.

Mirtazapine at a dose of 30 mg 1 time / day caused a small but statistically significant increase in MHO (international normalized ratio) in subjects treated with warfarin.
You can not exclude a more pronounced effect with a higher dose of mirtazapine. It is recommended to monitor MHO in case of treatment with warfarin in combination with mirtazapine.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Keep the drug out of reach of children at a temperature of no higher than 25 ° C.

Shelf life - 2 years.
Do not use after the expiration date.
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