Esprital - instructions for use, dose, side effects, contraindications

core: lactose monohydrate 88.8 mg, giprolase LH 21 30 mg, corn starch 56 mg, microcrystalline cellulose 30 mg, pregelatinized starch 30 mg, silicon dioxide colloid 1 mg, magnesium stearate 1.4 mg, talc 2.8 mg;

film sheath: hypromellose 4.8 mg, macrogol 6000 0.4 mg, titanium dioxide 0.5 mg, iron oxide oxide yellow 0.15 mg, iron oxide red oxide 0.05 mg, talc 0.1 mg.

Tablets 45 mg:

active substance: mirtazapine 45 mg;

Excipients:

core: lactose monohydrate 133.2 mg, giprolase LH 21 45 mg, corn starch 84 mg, microcrystalline cellulose 45 mg, pregelatinized starch 45 mg, silicon dioxide colloid 1.5 mg, magnesium stearate 2.1 mg, talc 4.2 mg;

film sheath: hypromellose 7.2 mg, macrogol 6000 0.6 mg, titanium dioxide 0.75 mg, talc 0.15 mg.

Description:

Tablets 30 mg:

Red-brown oblong film-coated tablets, with a risk for division on one side.

Tablets 45 mg:

White oblong coated tablets.

Pharmacotherapeutic group:antidepressant

ATX: & nbsp

N.06.A.X.11 Mirtazapine

Pharmacodynamics:

Mirtazapine is a centrally acting antagonist of presynaptic α₂-receptors, which increases neurotransmission in the central noradrenergic and serotonergic synapses. The increase in serotonergic neurotransmission is specifically mediated by the 5-NT₁, since the 5-H receptorsT₂ and 5-HT₃ are blocked by mirtazapine. It is assumed that both enantiomers of mirtazapine play a role in antidepressant activity: S(+) enantiomer by blocking the α₂ and 5-HT₂and R (-) enantiomer due to blocking 5-HT₃ receptors.The antagonistic effect of mirtazanin on histamine H₁-receptor is associated with sedative properties. The drug has almost no anticholinergic activity and in therapeutic doses has only limited effects (eg, orthostatic hypotension) on the cardiovascular system.

Pharmacokinetics:

Absorption

After oral administration mirtazapine quickly absorbed (bioavailability of about 50%), reaching a maximum concentration in the blood plasma after about 2 hours. Eating does not affect the pharmacokinetics of the drug.

Distribution

About 85% of mirtazapine binds to plasma proteins.

Biotransformation

Mirtazapine is actively metabolized and excreted by the kidneys and with bile within a few days. The main ways of its metabolism in the body are demethylation and oxidation followed by conjugation. Isozymes of the cytochrome P450 system (CYP2D6 and CYPIA2) participate in the formation of 8-hydroxy metabolite mirtazapine. while isoenzyme CYP3A4, presumably, determines education N-detylated and Noxidized metabolites.

Excretion

The mean half-life (T_1/2) is from 20 to 40 hours (rarely 65 hours). A shorter T_1/2is observed in young patients. The equilibrium concentration in the blood plasma is established after 3-5 days, after which no further accumulation of the drug is observed.

Linear / non-linear character of pharmacokinetics

Mirtazapine demonstrates linear pharmacokinetics when used in the recommended dose range.

Special patient groups

In patients with impaired renal or hepatic function, the clearance of mirtazapine may decrease.

Indications:Depressive states of various etiologies.

Contraindications:

- Hypersensitivity to mirtazapine or other components of the drug;

- simultaneous administration with monoamine oxidase inhibitors (MAO);

- lactose intolerance (lactase deficiency), hereditary intolerance to galactose and fructose, glucose-galactose malabsorption (the preparation contains lactose monohydrate);

- age to 18 years (efficacy and safety not proven).

Carefully:

Use with caution in patients:

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

- with hepatic or renal insufficiency:

- with heart disease (conduction disorder, angina pectoris or recent myocardial infarction);

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

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

- abusing drugs, with drug dependence, mania, hypomania;

- with violation of urination, including with benign prostatic hyperplasia;

- with acute closed-angle glaucoma and increased intraocular pressure;

- with diabetes mellitus;

- with simultaneous use with benzodiazepines, serotonergic drugs and other sedatives (see section "Interaction with other drugs").

Pregnancy and lactation:

The safety of the use of Esprital® in pregnancy is not established, so it can be used during pregnancy only if the benefit to the mother exceeds the potential risk to the fetus and under the supervision of 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.

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

Dosing and Administration:

Adults

The effective daily dose is usually from 15 to 45 mg; the initial dose is 15 or 30 mg. Usually mirtazapine begins to have its effect after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive result within 2-4 weeks. If the response is insufficient, the dose may be increased to the maximum. If there is no response within an additional 2-4 weeks, treatment should be discontinued.

Patients with depression should receive treatment for a sufficient period of time, at least for 6 months to make sure. that they have no symptoms.

Discontinue treatment with mirtazapine should be gradual in order to avoid withdrawal symptoms.

Elderly patients

The recommended dose for the elderly is similar to that for adult patients. To achieve a satisfactory effect and to ensure safety, increasing the dose to elderly patients should be carried out under close medical supervision.

Patients with impaired renal function

Mirtazapine clearance may decrease in patients with moderate or severe impairment of function of the nights (creatinine clearance (CK) <40 mL / min). This should be considered when administering mirtazapine to such patients.

Patients with impaired hepatic function

In patients with impaired hepatic function, the clearance of mirtazapine may decrease. This should be taken into account in the appointment of mirtazapine to such patients, in particular with severe impairment of liver function.

Side effects:

In patients with depression, there are a number of symptoms that are associated with the disease itself. Therefore, it is sometimes difficult to determine which symptoms are the result of the disease itself, and which symptoms are the result of treatment with mirtazapine.

The most frequent adverse reactions that were observed in more than 5% of patients who received mirtazapine in randomized, placebo-controlled trials (see information below), there were drowsiness, sedation, dry mouth, weight gain, increased appetite, dizziness and fatigue.

In all randomized, placebo-controlled trials, adverse reactions to mirtazapine. The meta-analysis included 20 studies with a planned duration of treatment of up to 12 weeks, including 150 patients (134 person-years) receiving mirtazapine doses up to 60 mg and 850 patients (79 person-years) receiving placebo. Extended phases of these studies were excluded to preserve the comparability of data with placebo.

Table 1 shows the frequency of adverse reactions in the categories that were observed in clinical trials statistically significantly during treatment with mirtazapine compared with placebo, with the addition of unwanted reactions noted in spontaneous reports and is based on the incidence of these events in clinical studies. The incidence of adverse reactions, noted and spontaneous reports, for which no case has been reported in randomized placebo-controlled trials in patients receiving mirtazapine, was classified as "frequency unknown."

Classes and systems of organs	Highly frequent (≥1/10)	Frequent (from ≥1/100 up to <1/10)	Infrequent (from ≥1 / 1000 to <1/100)	Rare (from ≥1 / 10,000 to <1/1000)	Frequency unknown (impossible calculate by available data)
DisordersI from the side of blood and lymphatic system					Inhibition of hemopoiesis (granulocytopenia, neutropenia, agranulocytosis, aplastic anemia and thrombocytesinging), eosinophilia.
Disorders from the endocrine system					Inadequate secretion antidiuretic a hormone.
DisordersI from the side of metabolism and nutrition	Increase masses bodies¹, increase in appetite¹				Hyponatremia
DisordersI psyche		Notordinary dreams. confusion consciousnesses anxiety^2,5, insomnia^3,5	Nightmares², mania, agitation², hallucinations, psychomotor agitation (including number of akatiziI, hyperandMr.eziya)	Agpecthis	Suicidal thoughts⁶, suicidal behavior⁶
DisordersI from the nervous system	Drowsiness¹, sedation^1,4, headache²	Inhibition¹, dizziness. tremorse	Paresthesia², restless legs syndrome, fainting	Myoclonus	Seizures, serotonismnora new syndrome, paresthesia of the oral mucosa, dysarthria
DisordersI from vessels		Orthostatic hypotension	Decrease arterial pressures²
DisordersI gastrointestinal tract	Dry mouth	Nausea³, diarrhea, vomiting², constipation¹	Hypesesia of the oral mucosa	Pancreatite	Edema mucous shells cavityand mouth. increased salivation.
Disturbances from the liver and bile ducts				Increase activity of "hepatic transaminases"
Disturbances from the skin and subcutaneous tissues		Exanthema²			Stevens-Johnson syndrome, bullous dermatitis, multi-form erythema, toxic epidermal necrolysis
Disturbances from musculoskeletal and connective tissue		Arthralgia, myalgia, back pain¹
General disorders		Peripheral edema¹, fatigue			Somnambulism, generalized edema, localized edema

¹ In clinical trials, these events were statistically significantly more frequent with mirtazapine than with placebo.

² In clinical trials, these events were more common with placebo than with mirtazapine, but the difference was not statistically significant.

³ In clinical trials, these events were statistically significantly more frequent with placebo than with mirtazapine.

⁴ Dose reduction does not usually lead to a decrease in drowsiness or excessive sedation, but may lead to a decrease in the effectiveness of the antidepressant.

⁵ In the treatment of antidepressants, anxiety and insomnia (which may also be symptoms of depression) may or may become more pronounced. On the background of mirtazapine therapy, there were cases of occurrence or increase of anxiety and insomnia.

⁶ There have been cases of suicidal intentions and suicidal behavior on the background of mirtazapine therapy or soon after discontinuation of therapy (see section "Special instructions").

A temporal increase in the activity of transaminases and gamma-glutamyltranspeptidase was observed in evaluating data from clinical trials (however, no adverse reactions associated with mirtazapine administration were reported that occurred with a significantly higher incidence than with placebo).

Overdose:

The current experience of observing cases of overdose with only mirtazapine indicates that the symptoms are usually mild. There was a CNS depression with disorientation and a long sedative effect, as well as tachycardia with a slight increase or decrease in blood pressure. However, when taking doses that are significantly higher than therapeutic doses, especially when overdosed a littlethere is a possibility of more serious consequences (including fatal outcome). In these cases, an ECG (electrocardiogram) also shows an elongation of the interval QT and the appearance of pirouette ventricular tachycardia (torsades de pointes).

In case of an overdose, appropriate symptomatic treatment should be performed to maintain the vital functions of the body. ECG monitoring should be performed. You should also enter Activated carbon or do a gastric lavage.

Children

In case of an overdose, children should take appropriate actions described for adults.

Interaction:

Pharmacodynamic interaction

Mirtazapine should not be used in combination with MAO inhibitors and within two weeks after discontinuation of treatment with MAO inhibitors (see "Contraindications"). Treatment MAO inhibitors should be started no earlier than two weeks after cessation of treatment with mirtazapine.

Simultaneous reception with other serotonergic drugs (L-tryptophan, triptans, tramadol, linezolid, methylene blue, selective serotonin reuptake inhibitors, venlafaxine, lithium preparations and preparations of St. John's Wort (Hypericum perforatum)) may lead to the development of serotonin syndrome (see section "Special instructions").

Mirtazapine can enhance the sedative properties of benzodiazepines and other sedatives (in particular, most antipsychotics, H antagonists₁histamine receptors, opioids).

Caution should be exercised when prescribing the above medicines together with mirtazapine and conducting more thorough clinical monitoring.

Mirtazapine can increase the depressive effect of alcohol on the central nervous system, so patients should be warned about the need to avoid drinking alcohol when taking mirtazapine.

Mirtazapine when used at a dose of 30 mg once a day caused a small but statistically significant increase in the international normalized relationship (MPO) 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.

With the simultaneous use of mirtazapine with other drugs that can cause lengthening of the interval QT (eg, some antipsychotics or antibiotics), as well as an overdose of mirtazapine increases the risk of lengthening the interval QT on ECG and / or occurrence of ventricular arrhythmias (eg, pirouette ventricular tachycardia).

Pharmacokinetic interaction

Carbamazepine and phenytoin (inducers of isoenzyme CYP3A4) increased the clearance of mirtazapine approximately twice, which led to a decrease in the concentrations of mirtazapine in blood plasma by 60% and 45%, respectively. When adding carbamazepine or another inducer of hepatic metabolism (eg rifampicin) to mirtazapine therapy, if necessary, increase the dose of mirtazapine. If you stop taking inducers of hepatic metabolism, you may need to reduce the dose of mirtazapine.

Application in combination with a potent inhibitor of isoenzyme CYP3A4 ketoconazole resulted in an increase in the maximum concentration in the blood plasma and AUC (area under the concentration-time curve) of mirtazapine by approximately 40% and 50%, respectively.

When applying at combination with cimetidine (a weak inhibitor of isoenzymes CYP1A2, CYP2D6 and CYP3A4) the average concentration of mirtazapine in blood plasma increases by more than 50%. Caution should be exercised when using mirtazapine in combination with potent inhibitors of isoenzyme CYP3A4, HIV protease inhibitors, azole antifungal drugs, erythromycin, cimetidine or nefazodone. If necessary, reduce the dose of mirtazapine.

In studies on the study of interactions mirtazapine did not affect the pharmacokinetics of paroxetine, amitriptyline, risperidone, or lithium preparations.

Special instructions:

Suicide / suicidal thoughts or clinical worsening of the course of the disease

Any depressive disorder in itself increases the risk of suicidal thoughts and suicidal behavior. This risk persists until stable remission is achieved. Because the improvement may not occur during the first few weeks of therapy (or longer), the condition of the patients should be carefully monitored before the onset of improvement. Clinical observations show that the risk of suicide may increase in the early stages of recovery.

Patients who had a history of suicidal behavior, as well as patients who had marked suicidal intent prior to therapy, are at increased risk of suicidal thoughts or suicide attempts and should be closely monitored.

A meta-analysis of results from placebo-controlled clinical studies on the use of antidepressants in adult patients with mental disorders revealed a higher risk of suicidal behavior in patients receiving antidepressants compared with the placebo group in the age group under 25 years. Patients receiving antidepressant therapy (especially those at high risk) should be closely monitored, especially at the beginning of therapy, and also in case of dose adjustment. Patients (as well as caregivers) should be warned about the need to detect any signs of clinical impairment, suicidal behavior, suicidal thoughts or unusual behavior in a timely manner, as well as the need to immediately notify the physician of the appearance of these symptoms.

Taking into account the possibility of suicide, especially at the beginning of therapy, the patient should be given the least amount of tablets to reduce the risk of overdose.

Inhibition of bone marrow function

When mirtazapine was used, there were cases of oppression of bone marrow functions, usually manifested in the form of granulocytopenia or agranulocytosis.

In rare cases, reversible agranulocytosis was noted in clinical trials, agarulocytosis was registered in very rare cases during post-registration observation, and in most cases it was also reversible, but several deaths were noted, which were registered mainly in patients older than 65 years. The doctor should carefully treat (and inform the patient) symptoms such as fever, sore throat, stomatitis, and other signs of flu-like syndrome, if such symptoms appear, stop treatment and make a blood test.

Jaundice

When there are signs of jaundice, treatment should be discontinued.

Conditions requiring medical attention

It should be prescribed with caution, as well as regular and careful monitoring of patients with the following conditions / diseases:

- 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 ESPRITAL preparation should be used with extreme caution in patients with epileptic seizures in the anamnesis. Treatment should be discontinued in the event of a development or an increase in the frequency of epileptic seizures.

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

- Heart disease, such as conduction disorders, angina pectoris and recently transferred) myocardial infarction. In these cases, the usual precautions are necessary when prescribing the drug ESPRITAL® and concomitant therapy.

- Low blood pressure.

- Diabetes. In patients with diabetes mellitus, antidepressants can affect the glucose level in the blood. You may need to adjust the dose of insulin and / or a dose of oral hypoglycemic drugs.

Careful observation is recommended

As with the use of other antidepressants, the following conditions can occur with the use of the drug ESPRITAL®:

- Perhaps worsening of the psychotic symptoms when using antidepressants for the treatment of patients with schizophrenia or with other psychotic disorders, paranoid ideas may intensify.

- The depressive phase of bipolar disorder on the background of treatment can be transformed to a manic phase.Patients with a history of mania / oligomania should be closely monitored. The drug ESPRITAL® should be abolished, the patient should be transferred to the manic phase.

- Although the drug ESPRITAL® is not addictive, the post-registration experience shows that a sharp cessation of treatment after prolonged use can sometimes lead to the appearance of withdrawal symptoms. Most of the symptoms of "cancellation" are weak and can be stopped on their own. The most commonly reported symptoms were: dizziness, agitation, anxiety, headache and nausea. Although they have been reported as symptoms of "withdrawal", it should be borne in mind that these symptoms can be associated with a major disease. Treatment with the drug ESPRITAL® is recommended to be discontinued gradually (see section "Dosage and Administration"),

- The drug ESPRITAL ® should be carefully administered to patients with urinary dysfunction, incl. with benign prostatic hyperplasia, as well as patients with acute closed-angle glaucoma and increased intraocular pressure (however, the negative effect of the drug ESPRITAL® is unlikely due to its very low anticholinergic activity).

- Akathisia / psychomotor agitation: the use of antidepressants is associated with the development of akathisia, which is characterized by a subjectively unpleasant or disturbing arousal 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.

- During the post-marketing application of mirtazapine, cases of prolongation of QT interval on ECG, ventricular tachycardia (including pirouette ventricular tachycardia) and sudden death were recorded. However, in most cases, these symptoms were noted against an overdose or in patients with other risk factors for prolonging the QT interval, including the simultaneous administration of two or more drugs causing prolongation of the QT interval (see "Interactions with Other Drugs" and "Side-Effects" ). Caution should be exercised in prescribing ESPRITAL® to patients with cardiovascular disease, as well as if there is an extended history of QT in the family history, or with concomitant therapy with other drugs that may cause prolongation of the QT interval.

Hyponatremia

When using mirtazapine, extremely rare cases of hyponatremia are described. Patients at risk (elderly patients or patients taking medications that can cause hyponatraemia) should be cautioned with ESPRITAL®.

Serotonin syndrome

With the simultaneous use of selective serotonin reuptake inhibitors and other serotonergic drugs, serotonin syndrome may occur (see section "Interaction with Other Drugs"). Symptoms of serotonin syndrome can be fever, stiffness, myoclonus. a disorder of the autonomic nervous system with possible rapid fluctuations in vital indicators of the functional state of the organism, a change in the mental state, including confusion, irritability and intense arousal, progressing into a disorder of consciousness and to whom. Care should be taken and careful clinical control should be carried out while taking these drugs with the preparation ESPRITAL. If such symptoms appear, discontinue treatment with ESPRITAL ® and begin symptomatic treatment.

Post-registration experience of the drug shows that serotonin syndrome in patients who receive monotherapy with mirtazapine appears very rarely (see the "Side effect" section).

Application in elderly patients

Elderly patients are usually more sensitive to therapy, especially to undesirable effects of antidepressants. In clinical studies of mirtazapine, it was noted that the frequency of detection of adverse reactions in elderly patients did not differ from that in patients in other age groups.

Patients should avoid the use of alcoholic beverages during treatment with the drug ESPRITAL®.

The preparation ESPRITAL® contains lactose monohydrate, therefore, patients with rare congenital conditions accompanied by galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine (see the section "Contraindications").

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

During treatment with Esprital®, avoidance of potentially hazardous activities requiring high rates of psychomotor reactions should be avoided,such as driving a car or controlling machinery.

Form release / dosage:

The film-coated tablets are 30 mg and 45 mg.

Packaging:

Tablets 30 mg: For 10 tablets in a blister of PVC / PVDC / Al. For 3 blisters in a cardboard box together with instructions for use.

Tablets 45 mg: For 10 tablets in a blister of PVC / PVDC / Al. For 3 or 10 blisters in a cardboard box along with instructions for use.

Storage conditions:

Does not require special storage conditions.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000697

Date of registration:20.03.2012

Expiration Date:Unlimited

Date of cancellation:2017-11-14

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Representation: & nbspZENTIVA PHARMA, LLCZENTIVA PHARMA, LLC

Information update date: & nbsp14.11.2017

Illustrated instructions

Instructions

Esprital® (Esprital®)