Ketilept

Pharmacological properties of the drug Ketilept

Pharmacodynamics. Quetiapine is an atypical antipsychotic drug that has an antagonistic effect on brain neurotransmitter receptors. Quetiapine has an affinity for serotonin (5HT1A and 5HT2), dopamine (D1 and D2), histamine (H1) and adrenergic (α1 and α2) receptors; higher affinity for 5HT2 receptors than for D1 and D2 receptors. Quetiapine also has a high affinity for histaminergic (H1) and α1-adrenergic receptors and a lower affinity for α2 receptors, while having no noticeable affinity for muscarinic cholinergic or benzodiazepine receptors. The mechanism of action of quetiapine, like other antipsychotic drugs, is unknown. Drowsiness during the action of quetiapine can be explained by its high affinity for histamine (H1) receptors. Similarly, orthostatic hypotension during quetiapine administration may be explained by its high affinity for α1-adrenergic receptors. Pharmacokinetics . After oral administration, quetiapine is rapidly absorbed into the gastrointestinal tract. The maximum concentration in blood plasma is observed after 1.5 hours. Food intake affects the bioavailability of quetiapine. Quetiapine is widely distributed in the body; its apparent volume is 10±4 l/kg. At therapeutic concentrations, 83% of the drug binds to blood plasma proteins. Clinical studies have shown that quetiapine is effective when used twice a day. Although the half-life of quetiapine is almost 7 hours, positron emission tomography data show that 5HT2 and D2 receptor occupancy is maintained for up to 12 hours after a single dose of quetiapine. Quetiapine is significantly metabolized in the liver; the main routes of its biotransformation are sulfonic oxidation and oxidation. In vitro , it has been shown that the main enzyme in the cytochrome P450-mediated metabolism of quetiapine is CYP 3A4. The main metabolites that are formed in the body do not have important pharmacological activity. After oral administration of a single dose of 14C-labeled quetiapine, ≤5% of the ingested amount is excreted unchanged; this indicates the deep metabolism of quetiapine. Approximately 73% of the radioactivity is excreted in urine and 21% in feces. The pharmacokinetics of quetiapine are linear over the therapeutic dose range and are not significantly affected by gender or race. The average clearance of quetiapine in elderly patients is approximately 30–50% lower than in adult patients aged 18–65 years. In severe renal failure (creatinine clearance ≤30 ml/min/1.73 m2) and liver failure (alcoholic cirrhosis), the average clearance of quetiapine is reduced by approximately 25%.

Quetiapine

Children and adolescents (ages 10 to 17 years)

Quetiapine is not indicated for use in children and adolescents under 18 years of age due to insufficient data on use in this age group. According to the results of clinical studies of quetiapine, some side effects (increased appetite, increased serum prolactin concentrations, vomiting, runny nose and fainting) were observed with a higher frequency in children and adolescents than in adult patients. Some adverse events (AEs) may have different consequences in children and adolescents compared to adult patients. An increase in blood pressure was also noted, which was not observed in adult patients. Changes in thyroid function have also been observed in children and adolescents. The effects on growth, puberty, mental development and behavioral reactions with long-term use (more than 26 weeks) of quetiapine have not been studied.

In placebo-controlled studies in children and adolescents with schizophrenia and mania in bipolar disorder, the incidence of advanced EPS was higher with quetiapine compared with placebo.

Suicide/suicidal ideation or clinical worsening

Depression in bipolar disorder is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicide-related events). This risk persists until significant remission occurs. Because it may take several weeks or more for the patient's condition to improve from the start of treatment, patients should be under close medical supervision until improvement occurs.

According to generally accepted clinical experience, the risk of suicide may increase in the early stages of remission. Patients (especially those at increased risk for suicide) and their caregivers should be warned to monitor for clinical worsening, suicidal behavior or thoughts, unusual changes in behavior, and to seek immediate medical attention if these occur.

In clinical trials in depressed patients with bipolar disorder, the risk of suicide-related events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18–24 years; 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo in patients over 25 years of age.

Other mental disorders for which quetiapine is prescribed are also associated with an increased risk of suicide-related events. In addition, such conditions may be comorbid with a depressive episode. Thus, the precautions used when treating patients with a depressive episode should also be taken when treating patients with other mental disorders.

If quetiapine therapy is abruptly discontinued, the potential risk of suicide-related events should be taken into account.

Patients with a history of suicidal events, as well as patients who clearly express suicidal thoughts before starting therapy, are at increased risk of suicidal intent and suicide attempts and should be carefully monitored during treatment.

An FDA meta-analysis of placebo-controlled studies of antidepressants, summing up data from approximately 4,400 children and adolescents and 7,700 adult patients with mental disorders, found an increased risk of suicidal behavior with antidepressants compared with placebo in children. adolescents and adult patients under 25 years of age. This meta-analysis does not include studies that used quetiapine.

In short-term, placebo-controlled studies across all indications and all age groups, the incidence of suicide events was 0.8% for both quetiapine (76/9327) and placebo (37/4845).

In these studies in patients with schizophrenia, the risk of suicide-related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients aged 18–24 years; 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients over 25 years of age; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under 18 years of age.

In patients with manic bipolar disorder, the risk of suicide-related events was 0% (0/60) for quetiapine and 0% (0/58) for placebo in patients aged 18–24 years; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients over 25 years of age; 1.0% (2/192) for quetiapine and 0% (0/90) for placebo in patients under 18 years of age.

Drowsiness

Drowsiness and associated symptoms such as sedation may occur during quetiapine therapy. In clinical studies involving patients with depression as part of bipolar disorder, somnolence usually developed during the first three days of therapy. The severity of this side effect was generally minor or moderate. If severe sleepiness develops, patients with depression as part of bipolar disorder may require more frequent visits to the doctor for 2 weeks after the onset of sleepiness or until symptoms improve. In some cases, discontinuation of quetiapine therapy may be necessary.

Patients with cardiovascular diseases

Caution should be exercised when prescribing quetiapine to patients with cardiovascular and cerebrovascular disease, and other conditions predisposing to hypotension.

Orthostatic hypotension may occur during quetiapine therapy, especially during dose titration at the beginning of therapy. Orthostatic hypotension and associated dizziness may increase the risk of accidental injury (fall), especially in older patients.

Patients should use caution until they adjust to these potential side effects. If orthostatic hypotension occurs, dose reduction or slower titration may be necessary.

Sleep apnea syndrome

Sleep apnea syndrome has been reported in patients taking quetiapine. Caution should be exercised when prescribing quetiapine to patients receiving drugs that have a depressant effect on the central nervous system, as well as patients with risk factors for sleep apnea (for example, overweight/obesity, male gender) or with a history of sleep apnea.

Seizures

There were no differences in the incidence of seizures in patients taking quetiapine or placebo. However, as with other antipsychotic drugs, caution is recommended when treating patients with a history of seizures with quetiapine.

Extrapyramidal symptoms

There was an increase in the incidence of EPS in adult patients with depression in the structure of bipolar disorder when taking quetiapine for depressive episodes compared to placebo.

While taking quetiapine, akathisia may occur, which is characterized by an unpleasant feeling of motor restlessness and the need to move, and is manifested by the patient's inability to sit or stand without moving. If such symptoms occur, the dose of quetiapine should not be increased.

Tardive dyskinesia

If symptoms of tardive dyskinesia develop, it is recommended to reduce the dose of the drug or gradually discontinue it. Symptoms of tardive dyskinesia may worsen or even occur after you stop taking the drug.

Neuroleptic malignant syndrome

While taking antipsychotic drugs, including quetiapine, neuroleptic malignant syndrome may develop. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, lability of the autonomic nervous system, and increased creatine phosphokinase activity. In such cases, it is necessary to discontinue quetiapine and carry out appropriate treatment.

Severe neutropenia and agranulocytosis

In short-term, placebo-controlled clinical trials of quetiapine monotherapy, cases of severe neutropenia (neutrophil count <0.5 x 109/L) without infection were reported infrequently. The development of agranulocytosis (severe neutropenia associated with infections) has been reported in patients receiving quetiapine in clinical trials (rare), as well as during post-marketing use (including death). Most of these cases of severe neutropenia occurred several months after initiation of quetiapine therapy. No dose-dependent effect was found.

Leukopenia and/or neutropenia resolved after discontinuation of quetiapine therapy.
A possible risk factor for the occurrence of neutropenia is a previous low white blood cell count and a history of drug-induced neutropenia. The development of agranulocytosis was also noted in patients without risk factors. The possibility of neutropenia should be considered in patients with infection, especially in the absence of obvious predisposing factors, or in patients with unexplained fever; these cases should be managed in accordance with clinical guidelines. In patients with a neutrophil count <1.0 x 109/L, quetiapine should be discontinued. The patient should be observed for possible symptoms of infection and the neutrophil level should be monitored (until the level exceeds 1.5 x 109/L).

Use of the drug Ketilept

Ketilept should be taken 2 times a day with meals or regardless of meals. Adults. The total daily dose in the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). Starting from the 4th day, the usual effective daily dose of Ketilept is 300 mg. Depending on the clinical response and tolerability of each patient, the dose can be adjusted between 150 and 750 mg/day. The safety of daily doses of 800 mg has not been assessed in clinical studies. For the treatment of acute manic episodes in bipolar disorders: the total daily dose in the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4). th day). From the 6th day, it is possible to increase the dose by no more than 200 mg/day until the maximum is reached (800 mg/day). Depending on the clinical response and tolerability of each patient, the dose can be adjusted ranging from 200 to 800 mg/day. The usual effective dose ranges from 400 to 800 mg/day. Elderly patients. Like other antipsychotic drugs, Ketilept should be used with caution in elderly patients, especially at the beginning of treatment. Elderly patients are recommended to first prescribe the drug at a dose of 25 mg/day, and then increase the dose by 25–50 mg/day until an effective dose is reached, which is usually lower than in young patients. In clinical studies, oral clearance of quetiapine may be reduced by 30–50% in patients aged ≥65 years, which may require dose adjustments. As in elderly patients, slow dose titration and reduced doses are recommended in debilitated patients or those susceptible to hypotensive reactions. Children and teenagers. The effectiveness and safety of quetiapine in children and adolescents has not been established. In case of renal dysfunction. Despite a 25% decrease in the clearance of quetiapine after oral administration of the drug in patients with severe renal failure (creatinine clearance 10–30 ml/min/1.73 m2), clinical studies have shown that in patients with normal renal function and patients with kidney diseases, plasma levels of the drug did not differ after taking equal doses of quetiapine. Therefore, there is no need to change the dose of Ketilept. Liver dysfunction. Quetiapine is significantly metabolized in the liver; its clearance in patients with liver disease is 25% lower than in patients with normal liver function. Therefore, if liver dysfunction is diagnosed, especially at the beginning of the course of treatment, it may be necessary to change the dose of the drug. It is recommended to start treatment with 25 mg of the drug per day, then increase the dose by 25–50 mg every day until an effective dose is reached, depending on the patient’s clinical response and individual tolerance. Maintenance therapy. Despite the lack of sufficient data on the possible duration of treatment with quetiapine in patients with schizophrenia, the effectiveness of maintenance therapy with other antipsychotic drugs has been established. Therefore, it is recommended to continue taking Ketilept to such patients; To maintain remission, it is advisable to use the lowest dose. Patients should be periodically assessed to determine the need for maintenance therapy. Resumption of an interrupted course of treatment in patients previously treated with quetiapine. If it is necessary to restart treatment with Ketilept in patients who have previously interrupted quetiapine therapy, the following is recommended: when resuming therapy less than 1 week after discontinuation of Ketilept, the drug can be continued at the dose used for maintenance therapy. When resuming therapy in patients who have not received Ketilept for 1 week, the rules for initial dose selection should be followed and the effective dose should be determined based on the patient’s clinical response. Transition from therapy with other antipsychotic drugs. There are no data on the specifics of switching from other antipsychotic drugs to quetiapine, as well as on the combined use of quetiapine with other antipsychotic drugs. Although some people with schizophrenia can be stopped immediately from the antipsychotic they are taking, most patients need to be tapered off gradually. In all cases where switching from one drug to another requires the simultaneous use of 2 antipsychotic drugs, this period of combined use should be reduced if possible. When transferring patients with schizophrenia from long-acting antipsychotic drugs to Ketilept, its use should be started at the time of the next scheduled dose. The need for continued therapy with a drug intended to treat the extrapyramidal side effects of a previous long-acting antipsychotic should be periodically assessed.

Use during pregnancy and breastfeeding

Category C. The safety and effectiveness of quetiapine during pregnancy has not been established.
The use of Ketilept® during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus.

It is unknown whether quetiapine is excreted in breast milk. If it is necessary to use the drug Ketilept® during lactation (breastfeeding), the issue of stopping breastfeeding should be decided.

Use for liver dysfunction

The drug should be used with caution in patients with liver failure.

For patients with hepatic impairment, it is recommended to initiate therapy with 25 mg/day, then increase the dose daily by 25-50 mg until an effective dose is achieved, depending on the patient's clinical response and individual tolerability.

Use for renal impairment

In patients with renal impairment, it is recommended to initiate therapy with 25 mg/day, then increase the dose daily by 25-50 mg until an effective dose is achieved, depending on the patient's clinical response and individual tolerability.

Use in children

Contraindication: children's age (efficacy and safety have not been established).

Use in elderly patients

The drug should be used with caution in elderly patients.

special instructions

Cardiovascular diseases

Ketilept® should be used with caution in patients with diagnosed cardiovascular disease, cerebrovascular disease, or other conditions predisposing to arterial hypotension.

Ketilept® may cause orthostatic hypotension, especially during the initial period of dose adjustment; it occurs more often in older than younger patients.

There was no relationship between quetiapine and an increase in the QTc interval. However, when prescribing quetiapine simultaneously with drugs that prolong the QTc interval, caution must be exercised, especially in elderly patients.

Seizures

There were no differences in the incidence of seizures in patients taking Ketilept® or placebo. However, as with other antipsychotic drugs, caution is recommended when treating patients with a history of seizures.

Tardive dyskinesia

Ketilept®, like other antipsychotic drugs, can cause tardive dyskinesia with long-term use. If signs and symptoms of tardive dyskinesia occur, dose reduction or discontinuation of the drug should be considered.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome may be associated with antipsychotic treatment. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, instability of the autonomic nervous system, and increased CPK levels. In such cases, Ketilept® should be discontinued and appropriate treatment administered.

Sudden withdrawal reactions

Acute withdrawal symptoms (including nausea, vomiting, insomnia) have been described in very rare cases after abrupt cessation of high-dose antipsychotic drugs. Relapses of symptoms of psychosis and the appearance of disorders associated with involuntary movements (akathisia, dystonia, dyskinesia) are possible. Therefore, if it is necessary to stop taking the drug, a gradual dose reduction is recommended.

Lactose intolerance

When preparing a diet for patients with lactose intolerance, it should be taken into account that film-coated tablets 25 mg, 100 mg, 150 mg, 200 mg and 300 mg contain lactose, respectively, 4.42 mg, 17.05 mg, 25.47 mg, 34.1 mg and 50.94 mg. The drug should not be prescribed to patients with rare hereditary disorders of galactose tolerance, hereditary lapp lactase deficiency or glucose-galactose malabsorption syndrome.

Taking into account that quetiapine primarily affects the central nervous system, the drug should be used with caution in combination with other drugs that have a depressant effect on the central nervous system or alcohol.

An association has been established between the use of low doses of quetiapine and a decrease in thyroid hormone levels (T4 and free T4). The maximum reduction occurred during the first 2 or 4 weeks of taking quetiapine, but no further reduction occurred with a long course of treatment. In almost all cases, discontinuation of quetiapine resulted in restoration of T4 and free T4 levels, regardless of the duration of treatment. Less significant reductions in T3 and reverse T3 were observed only with higher doses of quetiapine. Levels of TSH and TSH (thyroxine-binding globulin) remained unchanged. No clinically significant hypothyroidism was detected.

Like other antipsychotics, quetiapine may cause QTc prolongation, but this effect was not consistent in clinical trials.

Impact on the ability to drive vehicles and machinery

Due to its effect on the central nervous system, Ketilept® may cause drowsiness. Therefore, in the first stages of treatment, for an individually determined period of time, the patient should be prohibited from driving motor vehicles or dangerous machinery. In the future, the degree of restrictions is set individually.

Side effects of the drug Ketilept

The most common side effects: drowsiness, dizziness, dry mouth, asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia. As with therapy with other antipsychotic drugs, loss of consciousness, neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema were observed while taking quetiapine. Side effects classified by body system occurred: very often (1/10); often (≤1/10 and 1/100); sometimes (≤1/100 and 1/1000); rare (≤1/1000); very rare (≤1/10,000). Blood and lymph system: often - leukopenia; sometimes - eosinophilia; very rarely - neutropenia. Immune system disorders: sometimes - hypersensitivity reactions. Metabolism: often - increase in body weight, increase in serum transaminases (ALAT, AST); very rarely - hyperglycemia, diabetes mellitus. Dysfunction of the nervous system: very often - dizziness, drowsiness; often - loss of consciousness; sometimes - epileptic seizures. Cardiac dysfunction: often - tachycardia. Vascular disorders: often - orthostatic hypotension. Impaired breathing and functions of the thoracic cavity and mediastinum : often - rhinitis. Gastrointestinal dysfunction: often - dry mouth, constipation, dyspepsia. Dysfunction of the reproductive organs and mammary glands: rarely - priapism. General disorders and tissue condition at the injection site: often - mild asthenia, peripheral edema; rarely - neuroleptic malignant syndrome. Laboratory tests : sometimes - increased levels of gamma GT5, triglycerides after meals, increased total cholesterol. Treatment with Ketilept was associated with a small dose-dependent decrease in thyroid hormone levels, namely total T4 and free T4. The maximum decrease in total and free T43 was recorded during the first 2–4 weeks of quetiapine therapy, without further decrease in hormone levels during prolonged treatment. In almost all cases, cessation of treatment resulted in a restoration of total T4 and free T4 levels, regardless of the duration of treatment. A slight decrease in total T3 was observed only at high doses. The level of thyroxine-binding globulin did not change and, accordingly, no increase in TSH levels was observed. No signs of hypothyroidism were observed while taking Ketilept. Like other antipsychotics, quetiapine may cause QTc prolongation. Reactions to sudden drug withdrawal have also been described.

Quetiapine (Ketilept, Quentiax, Seroquel, Quetiap)

The most common adverse reactions associated with taking the drug: drowsiness (17.5%), dizziness (10%), constipation (9%), dyspepsia (6%), orthostatic hypotension and tachycardia (7%), dry mouth (7% ), increased activity of “liver” enzymes in the blood serum (6%), increased concentrations of cholesterol and triglycerides in the blood plasma.

Taking quetiapine may be accompanied by the development of moderate asthenia, rhinitis and dyspepsia, and an increase in body weight (mainly in the first weeks of treatment). Quetiapine may cause orthostatic hypotension (accompanied by dizziness), tachycardia and, in some patients, syncope; these adverse reactions mainly occur during the initial period of dose selection (see section "Special Instructions"). Quetiapine therapy is associated with a small dose-dependent decrease in the concentration of thyroid hormones, in particular total T4 and free T4. The maximum decrease in total and free T4 was recorded in the 2nd and 4th weeks of quetiapine therapy, without a further decrease in hormone concentrations during long-term treatment. There were no further signs of clinically significant changes in thyroid-stimulating hormone concentrations.

With long-term use of quetiapine, there is a potential for the development of tardive dyskinesia. If symptoms of tardive dyskinesia occur, reduce the dose or discontinue further treatment with quetiapine. With abrupt withdrawal of high doses of antipsychotic drugs, the following acute reactions (withdrawal syndrome) may be observed: nausea, vomiting, and rarely, insomnia.

There may be cases of exacerbation of psychotic symptoms and the appearance of involuntary movement disorders (akathisia, dystonia, dyskinesia). Therefore, it is recommended to discontinue the drug gradually.

The following are the adverse reactions observed with the use of quetiapine and distributed among organs and systems:

From the nervous system: drowsiness, dizziness, headache, anxiety, asthenia, hostility, agitation, insomnia, akathisia, tremor, convulsions, depression, paresthesia, neuroleptic malignant syndrome (hyperthermia, muscle rigidity, changes in mental status, lability of the autonomic nervous system, increased activity of creatine phosphokinase), restless legs syndrome.

From the cardiovascular system: orthostatic hypotension, tachycardia, prolongation of the QT interval.

From the digestive system: dryness of the oral mucosa, nausea, vomiting, abdominal pain, diarrhea or constipation, increased activity of liver transaminases, jaundice, hepatitis.

From the respiratory system: pharyngitis, rhinitis.

Allergic reactions: skin rash, eosinophilia, angioedema, Stevens-Johnson syndrome, anaphylactic reactions.

Laboratory indicators: leukopenia, neutropenia, hypercholesterolemia, hypertriglyceridemia, decreased T4 concentration (first 4 weeks), hyperglycemia.

Other: lower back pain, chest pain, low-grade fever, weight gain (mainly in the first weeks of treatment), myalgia, dry skin, blurred vision, incl. blurred visual perception, decompensation of existing diabetes mellitus, priapism, galactorrhea.

Special instructions for the use of the drug Ketilept

Ketilept should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions that lead to hypotension. Ketilept may cause orthostatic hypotension, especially during the initial dose adjustment period; this is more common in older patients than in younger patients. Like other antipsychotic drugs, Ketilept is prescribed with caution to patients who have a history of epileptic seizures; under these conditions, the drug can significantly reduce the seizure threshold (for example, in Alzheimer's disease or in people aged 65 years). Ketilept, like other antipsychotics, can cause tardive dyskinesia with prolonged use. If signs and symptoms of tardive dyskinesia occur, dose reduction or discontinuation of Ketilept should be considered. Neuroleptic malignant syndrome is a potentially dangerous condition that occurs very rarely during treatment with antipsychotic drugs. Its clinical manifestations include increased temperature, changes in mental state, muscle rigidity, instability of autonomic functions (fluctuations in heart rate and blood pressure, sweating, arrhythmia), as well as increased CPK levels. In such cases, Ketilept should be discontinued and appropriate therapy should be prescribed. Acute withdrawal symptoms, including nausea, vomiting, and insomnia, are very rarely described after abrupt cessation of high-dose antipsychotic medications. Relapses of symptoms of psychosis and the appearance of disorders associated with involuntary movements (akathisia, dystonia and dyskinesia) are possible. Therefore, if it is necessary to stop taking the drug, a gradual dose reduction is recommended. When preparing a diet for patients with lactose intolerance, it should be taken into account that film-coated tablets contain lactose, respectively 4.42; 17.05 and 34.1 mg. This drug should not be used in patients with hereditary galactose intolerance, hereditary lactase deficiency, or glucose-galactose malabsorption syndrome. The ability to influence reaction speed when driving vehicles or working with other mechanisms. Due to its effect on the central nervous system, Ketilept may reduce the level of attention of patients. Therefore, in the first stages of treatment, for an individually determined period of time, the patient should be prohibited from driving motor vehicles or dangerous mechanisms. In the future, the degree of restrictions should be set for each patient individually.

Instructions for use KETILEPT®

Since quetiapine has several indications for use, its safety profile should be considered in relation to each patient's diagnosis and dosage of the drug.

Children and adolescents aged 10 to 18 years

Quetiapine is not recommended for children and adolescents under 18 years of age due to the lack of data supporting the use of quetiapine in this age group. In clinical studies with quetiapine, it was found that in addition to the known safety profile established in adults (see section Side effects), some side effects occurred with a higher frequency in children and adolescents compared to adult patients (increased appetite, increased prolactin levels serum, vomiting, rhinitis and syncope), and some side effects have variable significance in children and adolescents (eg, extrapyramidal symptoms and irritability), and one side effect has not previously been observed in clinical trials in adults (increased blood pressure).

Changes in thyroid function test results have also been observed in children and adolescents.

In addition, studies examining the effects of long-term use of quetiapine on growth and development did not exceed 26 weeks. The effect of long-term use of quetiapine on cognitive function and behavior is also unknown.

In placebo-controlled studies in children and adolescents with schizophrenia or manic bipolar disorder, quetiapine was shown to increase the incidence of extrapyramidal symptoms (EPS) compared with placebo (see Adverse Reactions section).

Suicide, suicidal ideation, or worsening clinical condition

Depression in bipolar disorder is associated with an increased risk of suicidal ideation, self-harm, and suicide risk. This risk persists until significant remission occurs. Since improvement may not occur during the first weeks, and possibly for a longer period, patients should be carefully monitored until improvement occurs. Clinical experience also suggests that suicide risk may increase early in the course of improvement.

In addition, clinicians should consider the possible risk of suicide following sudden discontinuation of quetiapine due to known risk factors for the disease being treated with quetiapine.

Other psychiatric disorders for which quetiapine is prescribed may also increase the risk of suicide. Moreover, these disorders may be comorbid with a major depressive episode. Therefore, the same precautions should be taken when treating patients with other psychiatric disorders as when treating patients with a major depressive episode.

Patients with a history of suicidal ideation or behavior, as well as those with significant suicidal ideation before treatment, are at increased risk for suicidal ideation and suicide attempts and should therefore be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders found an increased risk of suicidal behavior when comparing groups of patients receiving antidepressants compared with placebo in patients aged <25 years.

In the early stages of treatment, as well as after changing the dose of the drug, patients, especially those at risk, should be closely monitored.

Patients (and caregivers) should be warned to monitor for clinical worsening, suicidal behavior or ideation, or unusual changes in behavior, and to seek medical attention if these symptoms occur.

In shorter-term, placebo-controlled clinical trials of patients with major depressive episode due to bipolar disorder, an increased risk of suicide-related events was observed in young adult patients <25 years of age receiving quetiapine compared with those receiving placebo (3.0% vs 0). % respectively).

Misuse and Abuse

There have been reports of misuse or abuse. Caution should be exercised when prescribing quetiapine to patients with a history of alcoholism or drug abuse.

Risk of developing metabolic disorders

Based on the observed risk of worsening the metabolic profile in clinical studies, including changes in body weight, changes in lipids and blood glucose (hyperglycemia), metabolic parameters should be monitored at the start of treatment, and changes in these parameters should be monitored regularly as treatment progresses. Deterioration of these parameters should be adjusted based on clinical need (see section Side effects).

Extrapyramidal symptoms

In placebo-controlled clinical trials in adult patients, an increased incidence of extrapyramidal symptoms (EPS) was found compared with placebo in patients treated for major depressive episodes in bipolar disorders (see sections Side effects and Pharmacological effects).

The use of quetiapine has been associated with the development of akathisia with a subjectively unpleasant or depressing restlessness, a need to move, often accompanied by an inability to stand or sit quietly. These symptoms are more likely to develop during the first weeks of treatment. In patients with these symptoms, increasing the dose may harm them.

Tardive dyskinesia

If signs and symptoms of tardive dyskinesia develop, dose reduction or discontinuation of Ketilept® should be considered. Symptoms of tardive dyskinesia may worsen or appear for the first time when treatment is stopped (see Side effects section).

Drowsiness and dizziness

An association has been found between the use of quetiapine and drowsiness or related symptoms (eg, sedation) (see Adverse Reactions section). In clinical studies involving patients with bipolar depression, these symptoms developed during the first three days of treatment, and their intensity was generally mild or moderate. Patients with bipolar disorder who develop severe, severe sleepiness may need more frequent contact with their doctor for at least 2 weeks after the onset of sleepiness.

Orthostatic hypotension

Quetiapine may cause orthostatic hypotension and associated dizziness (see section Side effects), especially at the initial stage of dose selection; it occurs more often in older patients than in younger patients. This may increase the risk of accidental falls, especially in older patients, compared to younger ones. For patients with cardiovascular disease, a dose reduction or slower individual dose titration is recommended. Therefore, patients are advised to exercise caution before determining the effect of the drug on their body.

Cardiovascular diseases

Ketilept® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Quetiapine may cause orthostatic hypotension, especially during the initial dose titration period, so a dose reduction or slower dose titration should be considered. Slower dose titration is recommended in patients with cardiovascular disease.

Sleep apnea syndrome

Sleep apnea syndrome has been observed in patients receiving quetiapine. Quetiapine should be administered with caution to patients taking other medicinal products that inhibit the central nervous system and who currently have or have had a history of sleep apnea (eg, weight gain/obesity, male patients).

Epileptic seizures

In controlled clinical trials, no differences were found in the frequency of epileptic seizures in patients receiving quetiapine or placebo. There are no data on the frequency of seizures in patients with a history of seizures. As with other antipsychotic drugs, caution should be exercised when treating patients with a history of epileptic seizures (see Side Effects section).

Neuroleptic malignant syndrome (NMS)

Neuroleptic malignant syndrome can occur during treatment with antipsychotic drugs, including quetiapine (see section Side effects). Its clinical manifestations include fever, changes in mental status, muscle rigidity, instability of autonomic functions (inconsistent heart rate and blood pressure, sweating, arrhythmia), as well as increased levels of creatine phosphokinase. In such cases, Ketilpet® should be discontinued and appropriate drug therapy should be prescribed.

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count <0.5 x 109/L) was observed in clinical studies with quetiapine. Most cases of severe neutropenia developed within several months of starting treatment with quetiapine. There is no obvious dose dependence of this effect. Based on post-marketing experience, some cases have been fatal. Possible risk factors for the development of neutropenia include a history of low white blood cell count or neutropenia caused by other drugs. If the neutrophil count decreases to <1.0 x 109/L, quetiapine should be discontinued. Patients should be monitored for signs and symptoms of infection and neutrophil levels monitored until they exceed 1.5 x 109/L (see Side Effects and Pharmacological Actions).

The possibility of developing neutropenia should be considered in patients with infection or fever, especially in the absence of predisposing factors, which requires appropriate treatment. Patients should be informed to report signs/symptoms of agranulocyotosis/infection (fever, weakness, lethargy, or sore throat). In such patients, it is necessary to immediately determine the number of leukocytes and the absolute number of neutrophils, especially in the absence of predisposing factors.

Anticholinergic (muscarinergic effects)

Norquetiapine, the active metabolite of quetiapine, has moderate to strong affinity for various muscarinic receptor subtypes. This predetermines the possibility of developing anticholinergic side effects when using quetiapine in recommended doses, when used together with other drugs that have anticholinergic properties, as well as in overdose. Quetiapine should be used with caution in patients concomitantly receiving other drugs with anticholinergic properties. Quetiapine should also be prescribed with caution to patients who have or have previously had urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or similar conditions, increased intraocular pressure or angle-closure glaucoma (see sections Drug interactions, Side effects, Overdose and Pharmacological effects).

Interactions

(see also section Drug interactions)

The use of quetiapine concomitantly with a strong hepatic enzyme inducer, such as carbamazepine or phenytoin, significantly reduces the plasma concentrations of quetiapine, which may affect the effectiveness of treatment with this drug. In patients receiving a liver enzyme inducer, treatment with Quetiapine should only be initiated if the physician determines that the benefits of quetiapine outweigh the risk of discontinuing the liver enzyme inducer. It is important that any change in inducer dosage be gradual and, if necessary, replaced with a non-inducer drug such as sodium valproate.

Body mass

Weight gain has been observed in patients receiving quetiapine; changes in body weight should be monitored and adjusted as a clinically important change, in accordance with available guidelines for the use of antipsychotic drugs (see sections Side effects and Pharmacological effects).

Hyperglycemia

Hyperglycemia or exacerbation of pre-existing diabetes, sometimes accompanied by the development of ketoacidosis or coma, sometimes fatal, have been described in rare cases (see section Side effects). In some cases, this was preceded by an increase in body weight, which can be considered as a predisposing factor. Appropriate clinical monitoring is recommended in accordance with available guidelines for the use of antipsychotic drugs. Patients receiving antipsychotic drugs, including quetiapine, should be monitored for the development of signs and symptoms of hyperglycemia (polydipsia, polyuria, polyphagia and weakness), and patients with diabetes, as well as patients at risk of developing diabetes mellitus, should be regularly monitored for worsening glycemic control. control.

Lipids

Increases in triglycerides, LDL and total cholesterol, as well as decreases in HDL cholesterol, were observed in clinical studies with quetiapine (see Side Effects section). Changes in lipid levels should be monitored and corrected as clinically significant.

QT prolongation

In clinical trials in which the drug was used in accordance with the instructions for medical use, the use of quetiapine was not associated with persistent prolongation of the QT interval. However, in post-registration studies, prolongation of the QT interval was observed in therapeutic doses (see section Side effects) and in overdose (see section Overdose). Just as when prescribing other antipsychotic drugs, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases, when combining quetiapine with drugs that increase the QT interval (including other antipsychotic drugs), especially in elderly patients, patients with congenital long QT syndrome, heart failure, cardiac hypertrophy, hypokalemia, hypomagnesemia and in patients with a family history of QT interval prolongation.

Cardiomyopathy and myocarditis

In clinical studies and with the use of quetiapine in the post-registration period, there have been reports of the development of cardiomyopathy and myocarditis, however, a causal relationship with quetiapine has not been established. The appropriateness of treatment with quetiapine in patients with cardiomyopathy and myocarditis should be analyzed.

Sudden withdrawal reactions

Acute withdrawal symptoms, including insomnia, nausea, vomiting, headache, diarrhea, dizziness, and irritability, have been described after abrupt discontinuation of high-dose antipsychotic medications. Therefore, if it is necessary to stop taking the drug, it is recommended to gradually reduce the dose over one to two weeks (see section Side effects).

Elderly patients with dementia-related psychosis

Quetiapine is not approved for use in patients with psychosis associated with dementia.

An approximately 3-fold increase in the risk of adverse cerebrovascular events was observed in randomized placebo-controlled trials in populations with dementia with the use of some atypical antipsychotics. The mechanism for this increased risk is unknown. An increased risk cannot be excluded also with the use of other antipsychotics or in other patient populations. In placebo-controlled studies using quetiapine, the incidence of cerebrovascular adverse events per 100 patient-years in the quetiapine group was not greater than that in the placebo group. Quetiapine should be used with caution in patients with risk factors for stroke.

A meta-analysis of atypical antipsychotics found that older patients with dementia-related psychosis had an increased risk of death compared with placebo.

However, in two 10-week placebo-controlled studies of quetiapine in the same patient population (n=710; mean age 85 years, range 56-99 years), mortality in the quetiapine group was 5.5% versus 3.2% in the placebo group. In these studies, patients died from many causes that would be expected in this population. These data do not allow us to establish a causal relationship between quetiapine use and death in elderly patients with dementia.

Dysphagia

Dysphagia (see Side Effects section) and aspiration have been observed during treatment with quetiapine. Ketilept® should be used with caution in patients at risk of developing aspiration pneumonia.

Constipation and intestinal obstruction

Constipation is a risk factor for intestinal obstruction. There have been reports of constipation and intestinal obstruction while taking quetiapine (see section Side effects). Deaths have been reported in patients at increased risk of intestinal obstruction, including those concomitantly receiving drugs that inhibit intestinal motility, who did not inform the doctor about the development of constipation. Patients with intestinal obstruction require close monitoring and emergency medical attention.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been observed during treatment with antipsychotic drugs. Due to the fact that patients receiving antipsychotic drugs had acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Ketilept® and preventive measures should be taken.

Pancreatitis

Pancreatitis has been observed both in clinical studies and in post-marketing experience. Despite the fact that in the post-registration period, risk factors were not identified in all cases, many patients had factors against which pancreatitis could develop:

increased triglyceride levels (see section Special instructions), gallstones and alcohol consumption.

Additional Information

There are limited data on the use of quetiapine in combination with divalproex or lithium for moderate to severe episodes of mania. However, combination therapy was well tolerated (see sections Side effects and Pharmacological effects). These data revealed an additive effect at week 3.

Ketilept® contains lactose monohydrate

Since Ketilept® contains lactose monohydrate, this drug should not be prescribed to patients with rare hereditary disorders of galactose tolerance, hereditary lactose deficiency or glucose-galactose malabsorption syndrome.

Preclinical safety studies

In a series of in vitro

and
in vivo
no signs of genotoxicity were detected. The following abnormalities have not yet been confirmed in long-term clinical trials in laboratory animals at exposure levels achievable in clinical settings:

Given all these data, the benefit of quetiapine treatment must be weighed against the safety risk to the patient.

Impact on the ability to drive vehicles and operate machinery

Due to its effect on the central nervous system, Ketilept® may reduce the level of wakefulness of patients. Therefore, in the first stages of treatment, for an individually determined period of time, patients should be advised to refrain from driving vehicles and working with dangerous mechanisms. In the future, the degree of restrictions should be set for each patient individually.

Drug interactions Ketilept

Ketilept should be prescribed with extreme caution in combination with other drugs that act on the central nervous system. The combined use of Ketilept with phenytoin leads to increased clearance of quetiapine from plasma when administered orally, since phenytoin induces cytochrome P450 isoenzyme 3A4. Due to the combination of quetiapine (250 mg 3 times a day) and phenytoin (100 mg 2 times a day), the average clearance of quetiapine after oral administration increased 5 times. To correct symptoms of schizophrenia in patients receiving concomitant quetiapine and phenytoin, an increase in the dose of Quetylept or other hepatic enzyme inducers (for example, carbamazepan, barbiturates, rifampicin or glucocorticoids) may be required. In these cases, caution should be exercised when differentiating from phenytoin and/or switching to valproate, which does not have enzyme-inducing properties. Carbamazepine When combined with carbamazepine, the clearance of quetiapine was significantly increased. As a result of this interaction, the concentration of Ketilept in the blood plasma may decrease and there is a need to use the drug in higher doses. It should be noted that for the treatment of schizophrenia, the maximum recommended daily dose of Ketilept is 750 mg. Long-term use of higher doses is possible only after a careful assessment of the benefit/risk ratio for a particular patient. Combination use with ketoconazole (200 mg/day for 4 days), a strong inhibitor of the cytochrome P450 3A enzyme, after oral administration reduced the clearance of quetiapine by 84%, as a result of which the concentration of quetiapine in the blood plasma increased by an average of 235%. Therefore, caution should be exercised during the simultaneous use of Ketilept and ketoconazole and other cytochrome P450 inhibitors, azole antifungals and macrolide antibiotics (for example, itraconazole, fluconazole and erythromycin); necessary appropriate reduction in the dose of quetiapine. Regular daily use of cimetidine (400 mg 3 times daily for 4 days) resulted in up to a 20% reduction in the average clearance of quetiapine (150 mg 3 times daily) after oral administration. When using Ketilept with cimetidine simultaneously, there is no need to change the dose of Ketilept. Thioridazine (200 mg twice daily) increased the clearance of quetiapine (300 mg twice daily) by 65% after oral administration. The combined use of quetiapine (300 mg 2 times a day) with antipsychotics such as haloperidol (7.5 mg 2 times a day) or risperidone (3 mg 2 times a day) did not change the equilibrium pharmacokinetic parameters of quetiapine. Concomitant use of quetiapine (300 mg twice daily) with the antidepressant and CYP3A4 and CYP2D6 inhibitor fluoxetine (60 mg once daily) or the CYP2D6 inhibitor imipramine (75 mg twice daily) did not change the equilibrium pharmacokinetic parameters quetiapine. Effect of Ketilept on other drugs. Repeated daily administration of quetiapine (up to 750 mg/day in 3 divided doses) does not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine does not have an inhibitory effect on liver enzymes that are involved in the cytochrome P450-mediated metabolism of antipyrine. The combined use of quetiapine (250 mg 3 times a day) with lithium did not affect the pharmacokinetic parameters of lithium at steady state. The mean oral clearance of lorazepam (single dose 2 mg) was reduced by 20% while taking quetiapine (250 mg three times daily). Smoking does not affect the plasma clearance of quetiapine. Clinical studies have shown that quetiapine potentiates the effects of alcohol in patients with psychosis. Therefore, you should refrain from drinking alcohol during the course of treatment with Ketilept.

Ketilept®

Particular caution is required when prescribing Ketilept® in combination with other drugs acting on the central nervous system.

The results of an in vitro study showed that quetiapine and 9 of its metabolites in vivo are weak inhibitors of metabolic processes mediated by cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6 and 3A4). CYP3A4 is the main enzyme responsible for P-450-mediated metabolism of quetiapine.

Effect of other drugs on Ketilept®

Phenytoin

The combination of the drug Ketilept® with phenytoin leads to an increase in plasma clearance of quetiapine, because Phenytoin induces cytochrome P450 isoenzyme 3A4. The combination of quetiapine (250 mg three times daily) and phenytoin (100 mg twice daily) increased the mean clearance of quetiapine after oral administration by 5 times.

To correct symptoms of schizophrenia in patients receiving concomitant quetiapine and phenytoin, increased doses of Ketilept® or other liver enzyme inducers (for example, carbamazepine, barbiturates, rifampicin or glucocorticoids) may be required. In these cases, caution is required when discontinuing phenytoin and/or switching to valproate, which does not have enzyme-inducing properties.

Carbamazepine

Co-administration with carbamazepine significantly increased the clearance of quetiapine, which reduced the systemic exposure of quetiapine. Due to this interaction, higher doses of Ketilept® may be required.

P450 3A inhibitors

Co-administration with ketoconazole (200 mg per day for 4 days), a strong inhibitor of the cytochrome P450 3 enzyme, reduced the clearance of quetiapine after oral administration by 84%, resulting in an average increase in quetiapine plasma concentrations of 235%. Therefore, caution is required when combining Ketilept® with ketoconazole and other cytochrome P450 inhibitors, azole antifungals and macrolide antibiotics (for example, itraconazole, fluconazole and erythromycin); a corresponding reduction in the dose of quetiapine is necessary.

Cimetidine

Regular daily administration of cimetidine (400 mg three times daily for 4 days), which is a nonspecific enzyme inhibitor, resulted in a 20% reduction in the mean plasma clearance of quetiapine (150 mg three times daily) after oral administration. When using Ketilept® with cimetidine simultaneously, there is no need to change the dose of Ketilept®.

Thioridazine

Thioridazine (200 mg twice daily) increased the plasma clearance of quetiapine (300 mg twice daily) by 65% after oral administration.

Risperidone and haloperidol

The combination of quetiapine (300 mg twice daily) with the antipsychotic drug haloperidol (7.5 mg twice daily) or risperidone (3 mg twice daily) did not change the steady-state pharmacokinetics of quetiapine.

Fluoxetine and imipramine

The combination of quetiapine (300 mg twice daily) with the antidepressant and CYP3A4 and CYP2D6 inhibitor fluoxetine (60 mg once daily) or the known CYP2D6 inhibitor imipramine (75 mg twice daily) did not change the steady-state pharmacokinetics of quetiapine.

Effect of Ketilept® on other drugs

Antipyrine

Repeated daily administration of quetiapine (up to 750 mg per day with three doses) did not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine does not have a significant inhibitory effect on liver enzymes involved in cytochrome P450-mediated metabolism of antipyrine.

Lithium

The combination of quetiapine (250 mg three times daily) with lithium did not affect any of the pharmacokinetic parameters of lithium at steady state.

Lorazepam

The mean oral clearance of lorazepam (single dose 2 mg) was reduced by 20% while taking quetiapine (250 mg three times daily).

Smoking

did not affect the clearance of quetiapine from blood plasma.

Clinical studies have shown that quetiapine potentiates the cognitive and motor effects of alcohol

in patients with psychosis. Therefore, you should not drink alcohol during treatment with Ketilept®.

Ketilept overdose, symptoms and treatment

There is very little evidence of quetiapine overdose in clinical studies. Most of the reported symptoms were due to an increase in the known pharmacological effects of the drug, such as drowsiness, sedation, tachycardia and hypotension. There is no specific antidote for Ketilept. In case of severe intoxication, the possibility of the patient taking several drugs simultaneously should always be considered. Intensive care is recommended, including clearing the patient's airway, ensuring adequate oxygenation and ventilation, and monitoring and maintaining cardiovascular function. Enhanced medical surveillance and monitoring should continue until the patient recovers completely.