TESTOSTERONU PROPIONAT

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETILEPT

KETILEPT

(KETILEPT)

COMPOSITION:

active substance: quetiapine; 1 tablet contains 28.78 mg, 115.13 mg, and 230.26 mg of quetiapine fumarate, which corresponds to 25 mg, 100 mg, or 200 mg of quetiapine;

excipients: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate (type A), povidone, magnesium stearate, colloidal anhydrous silicon dioxide;

shell composition: Opadry II 33G28523 white (hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol, triacetin); Opadry II 33G24283 pink (for 200 mg tablets) (hypromellose, titanium dioxide (E 171), lactose monohydrate, macrogol, triacetin, iron oxide red (E 172), iron oxide yellow (E 172)).

PHARMACEUTICAL FORM.

Tablets, film-coated.

MAIN PHYSICOCHEMICAL PROPERTIES:

25 mg tablets: white or almost white color, round, biconvex, film-coated tablets, with engraving of a stylized letter "E" on one side and the number "201" on the other side of the tablet, without or almost without odor;

100 mg tablets: white or almost white color, round, biconvex, film-coated tablets, with engraving of a stylized letter "E" and the number "202" on one side of the tablet, without or almost without odor;

200 mg tablets: dark pink color, round, biconvex, film-coated tablets, with engraving of a stylized letter "E" and the number "204" on one side of the tablet, without or almost without odor.

PHARMACOTHERAPEUTIC GROUP.

Antipsychotic agents. Quetiapine. ATC code: N05A H04.

PHARMACOLOGICAL PROPERTIES.

MECHANISM OF ACTION.

Quetiapine is an atypical antipsychotic agent that has an antagonist effect on neurotransmitter receptors in the brain. Quetiapine and its active plasma metabolite, norquetiapine, interact with various types of neuromediator receptors.

Quetiapine and norquetiapine have an affinity for serotonin (5HT1A and 5HT2), dopamine (D1 and D2), histamine (H1), and adrenergic (α1 and α2) receptors; it has a higher affinity for 5HT2 receptors than for D1 and D2 receptors. This combination of receptor antagonism with greater selectivity for 5-HT2 receptors relative to D2 receptors is believed to contribute to the clinical antipsychotic effects and low propensity for extrapyramidal side effects of the Ketilept preparation compared to typical antipsychotic preparations.

Quetiapine and norquetiapine also have a high affinity for histaminergic (H1) and α1-adrenergic receptors, lower affinity for α2 receptors, but no significant affinity for muscarinic cholinergic or benzodiazepine receptors, while norquetiapine has moderate or high affinity for several subtypes of muscarinic receptors, which may explain the anticholinergic (muscarinic) effects.

The inhibition of norquetiapine (NET), as well as the partial agonist effect on 5HT1A receptors, may contribute to the therapeutic efficacy of the Ketilept preparation as an antidepressant.

The mechanism of action of quetiapine, like other antipsychotic agents, is unknown.

Somnolence during quetiapine action can be explained by its high affinity for histamine (H1) receptors.

Similarly, orthostatic hypotension during quetiapine administration can be explained by its high affinity for α1-adrenergic receptors.

PHARMACODYNAMICS.

It is known that quetiapine is active in tests for antipsychotic activity, such as conditioned reflex avoidance.

Quetiapine blocks the agonistic effect on dopamine, which is confirmed by the results of evaluating behavioral reactions or electrophysiological studies, and also increases the concentration of dopamine metabolites, neurochemical expression of D2 receptor blockade.

It is known that during preclinical studies, during which the tendency to develop extrapyramidal symptoms was checked, quetiapine had an atypical activity profile and differed from standard antipsychotic preparations.

Quetiapine after prolonged use did not lead to excessive sensitivity of dopamine D2 receptors.

It is known that quetiapine at doses effective for blocking dopamine D2 receptors caused only weak catalepsy.

For quetiapine, after its prolonged introduction, selectivity for the limbic system was demonstrated, which was manifested by the ability to block depolarization in A10 mesolimbic neurons, but not in A9 nigrostriatal neurons, where dopamine is contained.

CLINICAL SAFETY

It is known that during treatment with quetiapine, a decrease in thyroid hormone levels is possible, this effect is dose-dependent.

Cataract

It is known that in a clinical study evaluating the cataractogenic potential of quetiapine (200-800 mg/day) versus risperidone (2-8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity was not higher in the group of patients taking quetiapine (4%) compared to those receiving risperidone (10%) when using the preparation for at least 21 months.

There are data that in placebo-controlled studies with the participation of elderly patients suffering from psychosis associated with dementia, the frequency of adverse events from the cardiovascular system per 100 patient-years in the quetiapine group was not higher than in patients receiving placebo.

PHARMACOKINETICS.

ABSORPTION

After oral administration, quetiapine is rapidly absorbed in the gastrointestinal tract. The maximum concentration in plasma is reached after 1.5 hours. Food intake affects the bioavailability of quetiapine.

At steady state, the mean molar concentration of the active metabolite norquetiapine is 35% of the concentration of quetiapine.

The pharmacokinetics of quetiapine and norquetiapine within the approved dose range are linear.

DISTRIBUTION

About 83% of the drug binds to plasma proteins.

METABOLISM

Quetiapine is extensively metabolized in the liver; the main pathways of its biotransformation are sulfation and oxidation. The use of radiolabeled quetiapine revealed that less than 5% of quetiapine is not metabolized and is excreted unchanged in the urine or feces.

In vitro studies have shown that the main enzyme of quetiapine metabolism, mediated by cytochrome P450, is CYP3A4. The main metabolites formed in the body do not have significant pharmacological activity.

ELIMINATION

Clinical studies have shown that quetiapine is effective when used twice a day. Despite the fact that the half-life of quetiapine is almost 7 hours, data from positron emission tomography (PET) show that the occupancy of 5HT2 and D2 receptors is maintained up to 12 hours after a single dose of quetiapine.

After oral administration of a single dose of 14C-labeled quetiapine, less than 5% of the administered amount is excreted in an unchanged state; this indicates active metabolism of quetiapine in the liver. Approximately 73% of the radioactive label is excreted in the urine and 21% in the feces.

SPECIAL POPULATIONS.

SEX

The pharmacokinetics of quetiapine in women and men do not differ.

The pharmacokinetics of quetiapine is linear in the therapeutic dose range and does not significantly depend on sex or race.

ELDERLY PATIENTS

In elderly individuals, the mean clearance of quetiapine is approximately 30-50% lower than in adult patients aged 18-65 years.

PATIENTS WITH RENAL IMPAIRMENT

In patients with severe renal impairment (creatinine clearance less than 30 mL/min), the mean clearance of quetiapine in plasma is reduced by approximately 25%.

PATIENTS WITH HEPATIC IMPAIRMENT

In patients with liver damage (compensated alcoholic cirrhosis), the mean clearance of quetiapine in plasma is reduced by approximately 25%. Since quetiapine undergoes extensive metabolic breakdown in the liver, the concentration of quetiapine in plasma may increase in patients with impaired liver function, and therefore, dose adjustment may be required for patients in this group (see "Method of administration and doses").

CHILDREN

It is known that there are pharmacokinetic data obtained in children who took 400 mg of quetiapine twice a day. When receiving a therapeutic dose, the levels of the initial compound quetiapine in children and adolescents (10-17 years) were generally similar to those in adults, although Cmax in children was higher than in adults. AUC and Cmax for norquetiapine were higher, approximately 62% and 49% in children (10-12 years), and 28% and 14% in adolescents (13-17 years), respectively, compared to adults.

CLINICAL CHARACTERISTICS.

INDICATIONS.

Treatment of schizophrenia.

Treatment of bipolar disorders, including:

• Manic episodes of moderate to severe degree associated with bipolar disorders;
• Major depressive episodes associated with bipolar disorders.

Prevention of recurrences in patients with bipolar disorders, in whom manic episodes have been treated with quetiapine.

CONTRAINDICATIONS.

- Hypersensitivity to any component of the preparation;

- concurrent administration of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone (see "Interaction with other medicinal products and other types of interactions").

INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER TYPES OF INTERACTIONS.

Given that quetiapine primarily acts on the central nervous system, Ketilept should be used with caution in combination with other preparations that have a similar effect and with alcohol.

Quetiapine should be used with caution in combination with serotonergic medicinal products, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as the risk of developing serotonin syndrome, a potentially life-threatening condition, increases (see "Special features of application").

The preparation should be prescribed with caution to patients who are taking other medications that have anticholinergic (muscarinic) effects (see "Special features of application").

Cytochrome P450 (CYP) 3A4 is the enzyme that is primarily responsible for the metabolism of quetiapine. In a study of the interaction in healthy volunteers, the concomitant administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) caused an increase in the AUC of quetiapine by 5-8 times. Therefore, the concomitant administration of quetiapine with CYP 3A4 inhibitors is contraindicated. Also, it is not recommended to consume grapefruit juice during the period of treatment with quetiapine.

During a study of multiple-dose administration with the aim of evaluating the pharmacokinetics of quetiapine, which was prescribed before and during treatment with carbamazepine (a liver enzyme inducer), the concomitant administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced the systemic exposure to quetiapine (measured by the area under the AUC curve) to a level that was, on average, 13% of the exposure during the administration of quetiapine alone, although in some patients, a greater effect was observed. As a result of this interaction, lower plasma concentrations may be created, which may affect the effectiveness of Ketilept therapy. The concomitant administration of quetiapine and another liver enzyme inducer, phenytoin, caused an increase in the clearance of quetiapine by approximately 450%. Starting therapy with Ketilept in patients who are taking a liver enzyme inducer can only be done if the doctor believes that the benefits of using Ketilept outweigh the risks associated with discontinuing the liver enzyme inducer. It is important that any changes in the intake of the liver enzyme inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see "Special features of application").

The pharmacokinetics of quetiapine is not significantly altered by the concomitant administration of such antidepressants as imipramine (a known inhibitor of CYP 2D6) or fluoxetine (a known inhibitor of CYP 3A4 and CYP 2D6).

The pharmacokinetics of quetiapine is not significantly altered by the concomitant administration of risperidone or haloperidol. Concomitant administration of quetiapine and thioridazine leads to an increase in the clearance of quetiapine by approximately 70%.

When co-administered with cimetidine, the pharmacokinetics of quetiapine did not change.

The pharmacokinetics of lithium did not change when co-administered with quetiapine.

There are data that in a randomized study lasting 6 weeks, comparing the combination of lithium with quetiapine and placebo with quetiapine in adult patients suffering from acute mania, an increased frequency of extrapyramidal disorders (especially tremors), somnolence, and weight gain was observed in the group with the addition of lithium compared to the group with the addition of placebo.

In the pharmacokinetics of sodium valproate and quetiapine, no clinically significant changes were observed when they were co-administered. In a retrospective study involving children and adolescents who received sodium valproate, quetiapine, or a combination of these preparations, an increased number of cases of leukopenia and neutropenia were observed in the group that took both preparations compared to the groups that received these medicinal products separately.

Studies on the interaction with cardiovascular preparations have not been conducted.

Cautious use is recommended when co-administering quetiapine with medicinal products that disrupt electrolyte balance or prolong the QT interval.

In patients who used quetiapine, there were cases of false-positive results of enzyme immunoassay for the presence of methadone and tricyclic antidepressants. It is recommended to verify suspicious results of screening immunoassay using a suitable chromatographic method.

SPECIAL FEATURES OF APPLICATION.

Since Ketilept is indicated for the treatment of schizophrenia, bipolar disorder, and concomitant treatment of depressive episodes in patients with TDR, the safety profile of the preparation should be carefully considered in relation to the specific diagnosis and dose taken by the patient.

CHILDREN

Ketilept is not recommended for use in children and adolescents under the age of 18 due to the lack of data that would support its use in this age group. Clinical studies of quetiapine have shown that, in addition to the known safety profile established for adults (see "Adverse reactions"), the frequency of some adverse events is higher in children than in adults (increased appetite, increased prolactin level in serum, and extrapyramidal symptoms), and one phenomenon was found that had not been observed in studies involving adult patients (increased blood pressure). In addition, changes in thyroid function tests were observed in children and adolescents.

It should also be noted that the delayed effect of treatment with Ketilept on growth and sexual maturation has not been studied for a period of more than 26 weeks. The long-term impact on cognitive and behavioral development is unknown.

It is known that during placebo-controlled clinical studies involving patients of child and adolescent age, treatment with quetiapine was accompanied by an increased frequency of extrapyramidal symptoms (EPS) in patients who were treated for schizophrenia and bipolar mania (see "Adverse reactions").

SUICIDE/SUICIDAL THOUGHTS OR CLINICAL WORSENING

Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission is established. As improvement may not be observed during the first weeks of treatment or longer, patients should be closely monitored until such improvement appears. According to general clinical experience, the risk of suicide may increase during the early stages of improvement.

In addition, it is necessary to consider the potential risk of suicide-related events after sudden discontinuation of treatment with quetiapine due to known risk factors for the disease being treated.

Other mental disorders for which Ketilept is prescribed may also be associated with an increased risk of suicide-related events. Moreover, these disorders may occur simultaneously with depressive episodes.

When treating patients with other mental disorders, the same precautions should be taken as when treating patients with severe depressive episodes.

Patients who have had suicide-related events in their history or who demonstrate a significant level of suicidal thinking before starting therapy have a higher risk of developing suicidal thoughts or attempting suicide and should be under close supervision during treatment. A meta-analysis of antidepressants in adult patients with mental disorders showed an increased risk of suicidal behavior in patients under the age of 25.

Close monitoring of patients, particularly those at high risk, should be accompanied by pharmacological therapy, especially at the beginning of treatment and during subsequent dose changes. Patients (and caregivers) should be warned about the need to monitor for clinical worsening, suicidal behavior, or unusual changes in behavior and to seek medical help immediately if symptoms appear.

EXTRAPYRAMIDAL SYMPTOMS

During placebo-controlled studies, quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients who received treatment for episodes of major depression associated with bipolar disorder and major depressive disorder (see "Adverse reactions").

The use of quetiapine was associated with the development of akathisia, which was characterized by subjectively unpleasant or distressing restlessness and a need to move, often accompanied by an inability to sit or stand still. These phenomena are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may harm them.

TARDIVE DYSKINESIA

If signs and symptoms of tardive dyskinesia appear, the issue of reducing the dose or discontinuing the use of Ketilept should be considered. Symptoms of tardive dyskinesia may worsen, and even appear after discontinuation of therapy (see "Adverse reactions").

SOMNOLENCE AND DIZZINESS

Treatment with quetiapine is associated with somnolence and similar symptoms, such as sedation (see "Adverse reactions"). During clinical studies, treatment of patients with bipolar depression with such symptoms usually occurred within the first 3 days of treatment and was mostly mild to moderate in intensity. Regarding patients with bipolar depression and patients with depressive episodes in TDR, in whom somnolence occurs, monitoring may be required for 2 weeks after the appearance of somnolence or until the symptoms disappear, or it may be necessary to consider discontinuing treatment.

ORTHOSTATIC HYPOTENSION

Treatment with quetiapine was accompanied by orthostatic hypotension and associated dizziness in some patients (see "Adverse reactions"), which, like somnolence, usually occur during the period of dose titration. These phenomena may contribute to an increased frequency of accidental injuries (falls), especially among elderly patients. Therefore, patients should be advised to be careful while they are getting used to the possible effects of the medicinal product.

NIGHT APNEA SYNDROME

There have been reports of the development of night apnea syndrome in patients taking quetiapine, so Ketilept should be used with caution in patients with excess body weight/obesity, male patients, and patients receiving concomitant therapy with antidepressants.

CARDIOVASCULAR DISEASES

Ketilept should be used with caution in patients with known cardiovascular and cerebrovascular diseases or other conditions that may lead to arterial hypotension.

Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration, so in such cases, a decrease in dose or longer titration may be necessary.

CARDIOMYOPATHY AND MYOCARDITIS

Cardiomyopathy and myocarditis have been reported in clinical studies and during the post-marketing period; however, a causal relationship with quetiapine has not been established. The use of quetiapine should be re-evaluated in patients with suspected cardiomyopathy or myocarditis.

SEIZURES

In studies, no difference was found in the frequency of seizures in patients taking quetiapine and patients in the placebo group. There are no data on the frequency of seizures in patients with a history of epilepsy. As with the treatment of other antipsychotic agents, it is recommended to use the preparation with caution in patients with a history of seizures (see "Adverse reactions").

MALIGNANT NEUROLEPTIC SYNDROME

Malignant neuroleptic syndrome may be associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, changes in mental state, muscle rigidity, vegetative instability, and increased creatine phosphokinase levels. In such a case, the use of Ketilept should be discontinued, and appropriate treatment should be started.

SEROTONIN SYNDROME

Concomitant administration of Ketilept and other serotonergic medicinal products, such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome, a potentially life-threatening condition (see "Interaction with other medicinal products and other types of interactions").

If concomitant therapy with other serotonergic medicinal products is clinically justified, close monitoring of the patient is recommended, especially at the beginning of treatment and during dose increases. Symptoms of serotonin syndrome may include changes in mental state, vegetative nervous system instability, neuromuscular disorders, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, the issue of reducing the dose or discontinuing therapy should be considered, depending on the severity of the symptoms.

SEVERE NEUTROPENIA ANDAGRANULOCYTOSIS

Severe neutropenia (neutrophil count <0.5 × 10^9/L) has been rarely observed in clinical studies of quetiapine. Aggranulocytosis (severe neutropenia with infection) has been reported rarely among patients receiving quetiapine during clinical trials and in the post-marketing period (including cases with a fatal outcome). Most cases of severe neutropenia occurred within two months of starting quetiapine therapy. No clear dose relationship was established. During the post-marketing period, normalization of leukopenia and/or neutropenia occurred after discontinuation of quetiapine therapy. Possible risk factors for neutropenia include pre-existing decreased white blood cell count (WBC) and drug-induced neutropenia in history. However, some cases were observed in patients without pre-existing risk factors. Treatment with quetiapine should be discontinued if the neutrophil count in the blood is <1.0 × 10^9/L. Monitoring of neutrophil count should be performed until it exceeds 1.5 × 10^9/L (see "Adverse reactions").

It is necessary to consider the possibility of developing neutropenia in patients with existing infections, despite the absence of risk factors, as well as in patients with unexplained fever, and to take appropriate clinical measures.

It is necessary to advise patients to immediately report the appearance of signs/symptoms indicating agranulocytosis or infection (such as fever, weakness, fatigue, or sore throat) at any time during treatment with the Ketilept preparation. Such patients should undergo timely determination of white blood cell count and absolute neutrophil count (ANC), especially in the absence of contributing factors.

ANTICHOLINERGIC (MUSCARINIC) SYNDROME

Norquetiapine, the active metabolite of quetiapine, has moderate or high affinity for several subtypes of muscarinic receptors, which may explain the anticholinergic (muscarinic) syndrome. This contributes to the development of adverse reactions that reflect anticholinergic effects when quetiapine is used concomitantly with other preparations that have anticholinergic effects, especially in cases of overdose. Quetiapine should be used with caution in patients who are taking medications that have anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with urinary retention (urinary retention), significant prostatic hyperplasia, intestinal obstruction, increased intraocular pressure, or angle-closure glaucoma (see "Interaction with other medicinal products and other types of interactions", "Adverse reactions", "Pharmacodynamic properties", "Overdose").

INTERACTIONS

See also "Interaction with other medicinal products and other types of interactions".

Concomitant administration of quetiapine with a potent liver enzyme inducer, such as carbamazepine or phenytoin, significantly reduces the concentration of quetiapine in plasma, which may impair the effectiveness of quetiapine therapy. Treatment with Ketilept in patients who are taking a liver enzyme inducer can only be started if the doctor believes that the benefits of using Ketilept outweigh the risks associated with discontinuing the liver enzyme inducer. It is essential that any changes in the intake of the liver enzyme inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate).

INFLUENCE ON BODY WEIGHT

Weight gain has been reported during treatment with quetiapine, which, as with the use of antipsychotic preparations, should be monitored and clinically corrected.

HYPERGLYCEMIA

Hyperglycemia and/or the development or exacerbation of diabetes mellitus have sometimes been associated with quetiapine, including several cases with fatal outcomes (see "Adverse reactions"). There have been reports of several cases with prior weight gain, which may be a contributing factor. Appropriate clinical monitoring is recommended in accordance with existing guidelines for the use of antipsychotic agents. Patients treated with any antipsychotic agents, including quetiapine, should be monitored for the development of signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes or risk factors for diabetes should be regularly checked for worsening glucose control. Body weight should be constantly monitored.

LIPIDS

Increases in triglyceride levels, LDL cholesterol, and total cholesterol, as well as decreases in HDL cholesterol levels, have been observed in clinical studies of quetiapine (see "Adverse reactions"). In case of changes in lipid levels, appropriate treatment should be prescribed.

METABOLIC RISK

Given the identified risk of worsening metabolic profile, including changes in body weight, glucose levels (see "Hyperglycemia"), and lipid levels in the blood, which were observed during clinical studies, it is necessary to evaluate the patient's metabolic parameters at the beginning of treatment and regularly monitor changes in these parameters during the course of treatment. Deterioration of these parameters should be corrected, taking into account clinical feasibility.

PROLONGATION OF THE QT INTERVAL

During clinical studies and in accordance with the Instructions for Medical Use, quetiapine did not cause a persistent increase in absolute QT intervals. However, QT interval prolongation has been observed in cases of overdose. As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases or patients with a prolonged QT interval in their family history. Also, caution should be exercised when prescribing quetiapine with other medicinal products that are known to prolong the QT interval or when used concomitantly with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, hypertrophy of the heart, hypokalemia, or hypomagnesemia (see "Interaction with other medicinal products").

CARDIOMYOPATHY AND MYOCARDITIS

Cardiomyopathy and myocarditis have been reported during clinical studies and in the post-marketing period; however, a causal relationship with quetiapine has not been established. The use of quetiapine should be re-evaluated in patients with suspected cardiomyopathy or myocarditis.

SEVERE SKIN ADVERSE REACTIONS

Very rarely, severe skin adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with quetiapine, which can be life-threatening or fatal. SCARs are usually presented as a combination of symptoms such as widespread skin rash or exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia. If signs and symptoms of these severe skin reactions appear, quetiapine should be discontinued immediately, and alternative treatment should be considered.

WITHDRAWAL OF THE PREPARATION

Acute withdrawal symptoms, such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability, have been described after the sudden discontinuation of quetiapine. Therefore, it is recommended to gradually discontinue the preparation over a period of at least one to two weeks (see "Adverse reactions").

ELDERLY PATIENTS WITH PARKINSON'S DISEASE (XII)/PARKINSONISM

A popular retrospective analysis of the use of quetiapine for the treatment of patients with VDR showed an increased risk of death during the use of quetiapine in patients over 65 years old. These data were not confirmed when the data of patients with Parkinson's disease were not taken into account in the analysis results. Caution should be exercised if quetiapine is prescribed to elderly patients with PD.

Ketilept is not recommended for the treatment of psychosis associated with dementia.

In randomized placebo-controlled studies in patients with dementia, the use of some atypical antipsychotics was associated with an approximately three-fold increased risk of cerebrovascular adverse events. The mechanism of this increased risk is unknown. The increased risk cannot be excluded for other antipsychotics or for other patient populations. Ketilept should be used with caution in patients with risk factors for stroke.

According to a meta-analysis of atypical antipsychotics, it is known that elderly patients suffering from psychosis associated with dementia are at increased risk of a fatal outcome compared to placebo. However, according to two 10-week placebo-controlled studies of the use of quetiapine in the same populations (n = 710, age 83 years, range 56-99 years), the mortality rate in patients treated with quetiapine was 5.5% compared to 3.2% in the placebo group. The mortality rate during the studies was due to various causes, which are expected for this patient population. These data did not establish a causal relationship between quetiapine treatment and patient mortality in patients with dementia.

DYSphagia

Dysphagia has been reported with quetiapine. Caution should be exercised when using quetiapine in patients who are at risk of aspiration pneumonia (see "Adverse reactions").

CONSTIPATION AND INTESTINAL OBSTRUCTION

Constipation is a risk factor for the development of intestinal obstruction. During the use of quetiapine, cases of constipation and intestinal obstruction have been reported (see "Adverse reactions"). These reports include reports of fatal cases in patients who have a higher risk of developing intestinal obstruction, including those patients who are taking several medicinal products that reduce intestinal peristalsis and/or medicinal products that may not have been reported to cause symptoms of constipation.

VENOUS THROMBOEMBOLISM (VTE)

Venous thromboembolism (VTE) has been reported with the use of neuroleptic agents. Since patients using neuroleptics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during therapy with quetiapine, and preventive measures should be taken.

PANCREATITIS

Cases of pancreatitis have been reported during clinical trials and post-marketing use of quetiapine, but a causal relationship has not been established. In post-marketing reports, many patients had factors known to be associated with pancreatitis, such as increased triglycerides (see "Special features of application", subsection "Lipids"), gallstones, and alcohol consumption.

ADDITIONAL INFORMATION

Data on the use of quetiapine in combination with divalproex or lithium for manic episodes of moderate or severe degree are limited; however, combination therapy was well-tolerated (see "Adverse reactions" and "Pharmacodynamic properties"). These data showed an additive effect on the third week of treatment.

LACTOSE

Ketilept tablets contain lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not use this medicinal product.

Ketilept 25 mg contains 4 mg of lactose monohydrate per tablet.

Ketilept 100 mg contains 16 mg of lactose monohydrate per tablet.

Ketilept 200 mg contains 32 mg of lactose monohydrate per tablet.

MISUSE AND ABUSE

There have been reports of misuse and abuse of the preparation. Caution should be exercised when prescribing quetiapine to patients with a history of alcohol and drug abuse.

USE DURING PREGNANCY OR BREASTFEEDING.

PREGNANCY

First trimester

The safety and efficacy of quetiapine for the treatment of pregnant women have not been established. There is no evidence of a negative impact from studies on animals. The possible impact on the organs of the fetus has not been studied. According to information on several pregnancies during which quetiapine was used, the development of symptoms of neonatal abstinence was reported in newborns. Therefore, during pregnancy, Ketilept can be prescribed only if the expected benefit justifies the potential risk. In newborns whose mothers took quetiapine during pregnancy, withdrawal symptoms from the preparation were observed.

III TRIMESTER

Newborns whose mothers took antipsychotic preparations, including quetiapine, in the third trimester are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which can vary in severity and duration after birth. These adverse reactions have been observed, including agitation, hypertension, hypotension, tremor, somnolence, respiratory disorders, and feeding disorders. Such newborns should be under close supervision.

BREASTFEEDING

There are published reports that quetiapine penetrates human breast milk, although the extent of penetration of the preparation into milk is unknown. Women who are breastfeeding should preferably discontinue breastfeeding during treatment with quetiapine.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND OPERATE MACHINERY.

Given that the preparation primarily acts on the central nervous system, quetiapine may negatively affect activities that require mental alertness. Therefore, patients are not recommended to drive a car or operate other machinery until it is determined how sensitive they are to such an effect.

METHOD OF ADMINISTRATION AND DOSES.

For each indication, there are different dosing regimens. It is necessary to ensure that the patient is prescribed a dose that corresponds to their condition. The dose of the preparation and the duration of the course of treatment are determined by the doctor individually for each patient, depending on the indications and the severity of the disease. For oral administration. Ketilept can be taken regardless of food intake. Tablets should be swallowed whole, without breaking, chewing, or crushing them.

ADULTS

Treatment of schizophrenia

The preparation Ketilept should be taken twice a day. In the first 4 days of therapy, the daily dose is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. Starting from the 4th day, the dose should be increased to achieve the necessary clinical effect (within the range of 300 to 450 mg/day). Depending on the clinical efficacy and tolerability of the preparation, the daily dose of Ketilept may be from 150 mg to 750 mg. The maximum daily dose of Ketilept for the treatment of schizophrenia is 750 mg.

Treatment of manic episodes associated with bipolar disorders

The preparation Ketilept should be taken twice a day. The daily dose in the first 4 days of treatment is: 1st day - 100 mg, 2nd day - 200 mg, 3rd day - 300 mg, 4th day - 400 mg. Further, the dose should be increased (but not more than 200 mg per day) to 800 mg/day, starting from the 6th day of treatment. Depending on the clinical efficacy and tolerability of the preparation, the dose may be from 200 to 800 mg/day. The usual effective dose is within the range of 400 to 800 mg per day. The maximum daily dose of Ketilept for the treatment of manic episodes is 800 mg.

Treatment of depressive episodes associated with bipolar disorders

The preparation Ketilept should be used once a day before bedtime. The total daily dose for the first four days of treatment is 50 mg (on the 1st day), 100 mg (on the 2nd day), 200 mg (on the 3rd day), and 300 mg (on the 4th day). The recommended daily dose is 300 mg. In clinical studies, no additional benefit was observed in the group using 600 mg compared to the group using 300 mg (see "Pharmacological properties"). A dose of 600 mg may be effective for individual patients. Doses above 300 mg should be prescribed by a doctor with experience in treating bipolar disorder. Clinical studies show that for individual patients, in case of problems related to intolerance of the preparation, it is necessary to consider reducing the dose to a minimum of 200 mg.

Treatment of depressive episodes associated with bipolar disorder should be prescribed by a doctor with experience in treating bipolar disorder.

PREVENTION OF RECURRENCES IN PATIENTS WITH BIPOLAR DISORDERS

For the prevention of subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who responded to Ketilept during urgent treatment of bipolar disorder should continue treatment with Ketilept at the same prescribed dose before bedtime. The dose of Ketilept can be adjusted within the dose range of 300 to 800 mg/day, depending on the clinical response and tolerability of each individual patient (twice a day). It is essential to use the lowest effective doses for maintenance therapy.

ELDERLY PATIENTS

As with other antipsychotics and antidepressants, Ketilept should be used with caution in elderly patients, especially at the beginning of treatment and during dose selection. A more gradual titration of the dose of Ketilept may be necessary, and the daily therapeutic dose may be lower than that used in younger patients. The mean plasma clearance of quetiapine was reduced by 30-50% in elderly individuals compared to younger patients.

In patients over 65 years old with depressive episodes in bipolar disorder, safety and efficacy have not been studied.

RENAL IMPAIRMENT

There is no need to adjust the dose for patients with renal impairment.

HEPATIC IMPAIRMENT

Quetiapine is actively metabolized in the liver. Therefore, the preparation Ketilept should be used with caution in patients with known liver function disorders, especially during the initial period of dose selection. Treatment of patients with liver function disorders should be started with a dose of 25 mg/day. The dose can be increased daily by 25-50 mg/day to achieve an effective dose, depending on the clinical response and tolerability of each individual patient.

CHILDREN

Ketilept is not recommended for use in children due to the lack of data that would support its use in this age group.

OVERDOSE.

Symptoms

Data on overdose of quetiapine in clinical studies are limited. The manifestations and symptoms of overdose were a consequence of the enhancement of the known pharmacological effects of the preparation, such as somnolence and sedation, tachycardia, and arterial hypotension. Overdose may lead to prolongation of the QT interval, seizures, epileptic status, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation, coma, and fatal outcome. Patients with existing severe cardiovascular disease may have an increased risk of overdose effects (see "Special features of application").

Treatment

There is no specific antidote to quetiapine. In cases of pronounced intoxication, it is necessary to consider the need for comprehensive measures and intensive therapy, including restoration and maintenance of airway patency, ensuring adequate oxygenation and ventilation of the lungs, monitoring, and maintaining cardiovascular activity. Regarding this situation, published reports describe cases of relief of severe CNS reactions, including coma and delirium, with intravenous administration of physostigmine (1-2 mg) under continuous ECG monitoring. Physostigmine cannot be used in case of arrhythmia, blockage of the heart of any degree, or extension of the QRS complex.

In cases of persistent arterial hypotension during quetiapine overdose, appropriate measures should be taken, such as intravenous administration of fluids and/or sympathomimetics (it is necessary to avoid the use of adrenaline and dopamine, as stimulation of beta-adrenergic receptors can exacerbate hypotension in the presence of alpha-adrenergic receptor blockade caused by quetiapine).

Since prevention of absorption has not been studied in cases of overdose, it is necessary to consider the need for gastric lavage, which, if possible, should be performed within 1 hour after administration of the preparation (after intubation, if the patient is unconscious), but no later than 1 hour after taking the preparation, as well as the use of activated charcoal with a laxative.

Close medical monitoring and control should continue until the patient's full recovery.

Adverse Reactions

As with other antipsychotic medications, loss of consciousness, malignant neuroleptic syndrome, leukopenia, neutropenia, and peripheral edema have been reported during quetiapine administration.

The frequency of adverse events during quetiapine treatment is presented below (Table 1) according to the following classification: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), and unknown frequency (cannot be estimated from available data).

See the "Special Instructions" section.

Somnolence usually occurs within the first two weeks of treatment and usually disappears with continued quetiapine administration.

Asymptomatic elevations in transaminase levels (ALT, AST) or gamma-GT have been reported in some patients treated with quetiapine. These elevations were usually reversible with continued quetiapine treatment.

Like other antipsychotic medications that block alpha1-adrenergic receptors, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia, and syncope in some patients, especially during the initial dose titration period (see "Special Instructions" section).

The frequency of these adverse reactions was calculated based on post-marketing data from quetiapine immediate-release formulation.

Fasting glucose level ≥ 126 mg/dL (≥ 7.0 mmol/L) or postprandial glucose level ≥ 200 mg/dL (≥ 11.1 mmol/L) at least once.

An increased incidence of dysphagia was observed in quetiapine-treated patients compared to placebo only in clinical trials for bipolar depression.

Based on ≥ 7% increase in body weight compared to baseline. Occurs mainly during the first weeks of therapy in adults.

Withdrawal symptoms that were most frequently reported in short-term placebo-controlled monotherapy clinical trials, where withdrawal symptoms were evaluated: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions decreased substantially after one week post-therapy.

10. Triglyceride level ≥ 200 mg/dL (≥ 2.258 mmol/L) (patients ≥ 18 years) or ≥ 150 mg/dL (≥ 1.694 mmol/L) (patients < 18 years) at least once.

11. Cholesterol level ≥ 240 mg/dL (≥ 6.2064 mmol/L) (patients ≥ 18 years) or ≥ 200 mg/dL (≥ 5.172 mmol/L) (patients < 18 years) at least once. Increase in LDL cholesterol level ≥ 30 mg/dL (≥ 0.769 mmol/L) occurs very commonly. The mean value among patients with such an increase was 41.7 mg/dL (1.07 mmol/L).

See below.

Platelet count ≤ 100 × 10^9/L at least once.

According to reports of clinical trials on adverse reactions, increased creatine phosphokinase levels in the blood are not associated with malignant neuroleptic syndrome.

Prolactin level (patients > 18 years): > 20 mcg/L (> 869.56 pmol/L) males; > 30 mcg/L (> 1304.34 pmol/L) females – at any time.

May lead to falls.

HDL cholesterol: < 40 mg/dL (1.025 mmol/L) males; < 50 mg/dL (1.282 mmol/L) females at any time.

Number of patients whose QTc interval changed from < 450 ms to ≥ 450 ms with an increase of ≥ 30 ms. In quetiapine placebo-controlled studies, the mean change and the number of patients who had a shift to a clinically significant level were similar in the quetiapine and placebo groups.

Shift from > 132 mmol/L to ≤ 132 mmol/L at least at one examination.

Suicidal thoughts and behaviors have been reported during quetiapine therapy or immediately after discontinuation of the drug (see "Special Instructions" and "Pharmacological Properties" sections).

See the "Pharmacological Properties" section.

22. Decreased hemoglobin level to ≤ 13 g/dL (8.07 mmol/L) in males, ≤ 12 g/dL (7.45 mmol/L) in females, at least at one examination, was observed in 11% of patients treated with quetiapine in all studies, including open-label studies. For these patients, the mean maximum decrease in hemoglobin level at any time was -1.50 g/dL.

These events often occurred against a backdrop of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disease.

Based on shifts from normal baseline to potentially clinically significant values at any time after baseline in all studies. Shifts in total T4, free T4, total T3, and free T3 were < 0.8 × LLN (pmol/L) and shifts in TSH were > 5 mU/L at any time.

Based on increased incidence of vomiting in elderly patients (≥ 65 years).

Based on shifts in neutrophil count from ≥ 1.5 × 10^9/L initially to < 0.5 × 10^9/L at any time during treatment and based on the presence of patients with severe neutropenia (< 0.5 × 10^9) and infection during all quetiapine clinical trials.

Based on shifts from normal baseline to potentially clinically significant values at any time after baseline in all studies. Shifts in eosinophil count were > 1 × 10^9 cells/L at any time.

Based on shifts from normal baseline to potentially clinically significant values at any time after baseline in all studies. Shifts in leukocyte count were ≤ 3 × 10^9 cells/L at any time.

Based on reports of metabolic syndrome from all quetiapine clinical trials.

During clinical trials, some patients experienced an increase in more than one metabolic factor that negatively affects body weight, glucose, and lipids (see "Special Instructions" section).

See the "Use in Pregnancy or Lactation" section.

May occur during or shortly after the initiation of therapy and is associated with hypotension and/or syncope. The frequency of occurrence is based on reports of adverse reactions of bradycardia and related events observed in all quetiapine clinical trials.

Based on one retrospective non-randomized epidemiological study.

Cases of prolonged QT interval, ventricular arrhythmia, sudden unexplained death, cardiac arrest, and torsades de pointes have been reported with neuroleptic medications and are considered specific to this class of drugs.

Severe skin adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with quetiapine treatment.

Children

The above-mentioned adverse reactions observed in adults also occur in pediatric and adolescent patients (10-17 years).

Adverse reactions were observed during clinical trials with quetiapine in children and adolescents.

In Table 2 below, adverse reactions with a higher frequency of occurrence in pediatric and adolescent patients (10-17 years) or not observed in adult patients are presented.

Adverse reactions are arranged according to their frequency of occurrence using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); and very rare (< 1/10000).

1 Prolactin levels (patients < 18 years): > 20 mcg/L (> 869.56 pmol/L) in male patients; > 26 mcg/L (> 1130.428 pmol/L) in female patients at any time. Less than 1% of patients had a prolactin level increase > 100 mcg/L.

2 Based on shifts above clinically significant values (based on National Institutes of Health criteria) or increases > 20 mmHg for systolic or > 10 mmHg for diastolic blood pressure at any time in two short-term (3-6 weeks) placebo-controlled studies in children and adolescents.

3 Note: The frequency corresponds to that observed in adults, but irritability may be associated with different clinical manifestations in children and adolescents compared to adults.

4 See the "Pharmacodynamics" section.

Reporting Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf Life

5 years.

Storage Conditions

Store at a temperature not exceeding 25°C, out of reach of children.

Packaging

10 tablets in a blister pack; 3 or 6 blister packs in a carton.

Release Category

Prescription only.

Manufacturer

Egis Pharmaceutical Plant Co. Ltd., Hungary.

Manufacturer's Address

1165, Budapest, Bökényföldi street 118-120, Hungary.