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:
- Pigment deposition in the thyroid gland was observed in rats. In marmoset monkeys, follicular cell hypertrophy of the thyroid gland, a decrease in plasma T3 levels, a decrease in hemoglobin levels and the number of erythrocytes and leukocytes were found. Cases of lens opacities and cataracts have been reported in dogs.
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.
Ketilept®
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 the elderly.
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 100 mg, 200 mg and 300 mg contain lactose, respectively, 17.05 mg, 34.1 mg and 50.94 mg. This drug should not be used in patients with rare hereditary disorders of galactose intolerance, 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.
In controlled clinical studies of quetiapine, there were no cases of sustained severe neutropenia or agranulocytosis. During the observation period after registration of the drug, leukopenia and/or neutropenia resolved after discontinuation of quetiapine administration. Possible risk factors for leukopenia and/or neutropenia include a pre-existing low white blood cell count and a history of drug-induced leukopenia and/or neutropenia.
Like other antipsychotics with alpha1-adrenergic blocking activity, Ketilept® may cause orthostatic hypotension with dizziness, tachycardia and (in some patients) syncope, especially during the initial dose titration period.
In very rare cases, hyperglycemia and worsening of pre-existing diabetes have been observed while taking quetiapine.
A connection has been established between taking quetiapine and a decrease in thyroid hormone levels (T4 and free T4), caused by taking it in small doses. The maximum reduction occurred during the first two to four weeks of taking quetiapine, but no further reduction occurred with a long course of treatment. A less significant decrease in T3 and reverse T3 was observed only when taking quetiapine at higher doses. Levels of TSH and TSH (thyroxine-binding globulin) remained unchanged. In almost all cases, discontinuation of quetiapine resulted in restoration of T4 and free T4 levels, regardless of the duration of treatment. No clinically significant hypothyroidism was detected.
Use in pediatrics
The effectiveness and safety of quetiapine in children and adolescents has not been established.
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.
