Ketilept

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETILEPT® (KETILEPT®)

Composition:

Active substance: quetiapine;

1 tablet contains 28.78 mg, 115.13 mg or 230.26 mg of quetiapine fumarate, corresponding to 25 mg, 100 mg or 200 mg of quetiapine, respectively;

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

Coating 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. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: white or almost white, round, biconvex, film-coated tablets, with engraved stylized letter "E" on one side and number "201" on the other side, odorless or nearly odorless;

100 mg tablets: white or almost white, round, biconvex, film-coated tablets, with engraved stylized letter "E" and number "202" on one side, odorless or nearly odorless;

200 mg tablets: dark pink, round, biconvex, film-coated tablets, with engraved stylized letter "E" and number "204" on one side, odorless or nearly odorless.

Pharmacotherapeutic group. Antipsychotic agents. Quetiapine. ATC code: N05AH04.

Pharmacological Properties

Mechanism of Action

Quetiapine is an atypical antipsychotic agent that exerts antagonistic effects on neurotransmitter receptors in the brain. Quetiapine and its active human plasma metabolite, norquetiapine, interact with various types of neurotransmitter receptors.

Quetiapine and norquetiapine have affinity for serotonin (5HT1A and 5HT2), dopamine (D1 and D2), histamine (H1), and adrenergic (α1 and α2) receptors; they exhibit greater affinity for 5HT2 receptors than for D1 and D2 receptors. This combination of receptor antagonism, with higher selectivity for 5-HT2 receptors relative to D2 receptors, is considered responsible for the clinical antipsychotic effects of Ketilept® and its lower propensity for extrapyramidal side effects compared to typical antipsychotics.

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

Inhibition of the norepinephrine transporter (NET) by norquetiapine, as well as partial agonist activity at 5HT1A receptors, may contribute to the therapeutic efficacy of Ketilept® as an antidepressant.

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

Somnolence caused by quetiapine can be explained by its high affinity for histaminergic (H1) receptors.

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

Pharmacodynamics

Quetiapine is known to be active in tests of antipsychotic activity, such as conditioned avoidance response.

Quetiapine blocks dopamine agonist effects, as confirmed by behavioral response assessments or electrophysiological studies, and increases dopamine metabolite concentrations, indicating neurochemical D2 receptor blockade.

Preclinical studies assessing the potential for development of extrapyramidal symptoms have shown that quetiapine has an atypical activity profile and differs from standard antipsychotics.

Long-term administration of quetiapine does not lead to excessive sensitivity of dopaminergic D2 receptors.

Quetiapine, at doses effective in blocking dopaminergic D2 receptors, has been shown to cause only mild catalepsy.

With prolonged administration, quetiapine has demonstrated selectivity for the limbic system, evidenced by its ability to block depolarization in A10 mesolimbic neurons but not in A9 nigrostriatal neurons, where dopamine is located.

Clinical Safety

It is known that treatment with quetiapine may lead to a reduction in thyroid hormone levels; this effect is dose-dependent.

Cataract

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 no higher in the quetiapine group (4%) compared to the risperidone group (10%) after at least 21 months of treatment.

Data from placebo-controlled studies in elderly patients with psychosis associated with dementia indicate that the incidence of cardiovascular adverse events per 100 patient-years in the quetiapine group was not higher than in the placebo group.

Pharmacokinetics

Absorption

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

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

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

Distribution

Approximately 83% of the drug is protein-bound in plasma.

Metabolism

Quetiapine is extensively metabolized in the liver; the main biotransformation pathways are sulfoxidation and oxidation. Studies using radiolabeled quetiapine have shown that less than 5% of quetiapine is excreted unchanged in urine or feces.

In vitro studies have demonstrated that the primary cytochrome P450 enzyme involved in quetiapine metabolism is CYP3A4. The major metabolites formed in the body do not have significant pharmacological activity.

Excretion

Clinical studies have shown that quetiapine is effective when administered twice daily. Although the elimination half-life of quetiapine is approximately 7 hours, positron emission tomography (PET) data indicate that occupancy of 5HT2 and D2 receptors is maintained for up to 12 hours after a single dose.

After oral administration of a single dose of 14C-labeled quetiapine, less than 5% of the administered amount is excreted unchanged, indicating extensive hepatic metabolism of quetiapine. Approximately 73% of the radiolabeled dose is excreted in urine and 21% in feces.

Special Populations

Gender

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

Quetiapine pharmacokinetics are linear within the therapeutic dose range and are not significantly influenced by gender 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/1.73 m²) and hepatic impairment (alcoholic cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%.

Patients with Hepatic Impairment

In patients with liver disease (compensated alcoholic cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%. Since extensive metabolism of quetiapine occurs in the liver, plasma concentrations of quetiapine may increase in patients with hepatic impairment, and therefore dose adjustment may be required for this patient group (see section "Dosage and Administration").

Children

Pharmacokinetic data are available from children receiving 400 mg of quetiapine twice daily. At therapeutic doses, plasma levels of the parent 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 relapses in patients with bipolar disorders whose manic episodes have been treated with quetiapine.

Contraindications.

• Hypersensitivity to any component of the medicinal product;
• concomitant use of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone
  (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Since quetiapine primarily acts on the central nervous system, KetiLept® should be used with caution in combination with other agents having a similar effect and with alcohol.

Quetiapine should be used with caution in combination with serotonergic medicinal products, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as the risk of developing serotonin syndrome, a potentially life-threatening condition, may increase (see section "Special precautions for use").

The medicinal product should be prescribed with caution to patients receiving other drugs with anticholinergic (muscarinic) effects (see section "Special precautions for use").

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for quetiapine metabolism. In an interaction study in healthy volunteers, concomitant administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) resulted in a 5- to 8-fold increase in quetiapine AUC. Therefore, concomitant use of quetiapine with CYP 3A4 inhibitors is contraindicated. Grapefruit juice should also not be consumed during treatment with quetiapine.

In a multiple-dose study assessing the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant use of carbamazepine significantly increased quetiapine clearance. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to an average of 13% of exposure when quetiapine was administered alone, although a greater effect was observed in some patients. Due to this interaction, lower plasma concentrations may occur, which could affect the efficacy of KetiLept® therapy. Concomitant use of quetiapine and phenytoin (another microsomal enzyme inducer) resulted in an increase in quetiapine clearance by approximately 450%. Initiation of KetiLept® therapy in patients receiving a hepatic enzyme inducer should only be considered if the physician determines that the benefit of using KetiLept® outweighs the risks associated with discontinuation of the hepatic enzyme inducer. It is important that any changes in the use of the inducer be made gradually. If necessary, the inducer should be replaced with a non-inducer (e.g., sodium valproate) (see section "Special precautions for use").

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

The pharmacokinetics of quetiapine are not significantly altered when administered concomitantly with risperidone or haloperidol. Concomitant administration of quetiapine and thioridazine results in an increase in quetiapine clearance by approximately 70%.

No changes in quetiapine pharmacokinetics were observed when administered concomitantly with cimetidine.

The pharmacokinetics of lithium were not altered when administered concomitantly with quetiapine.

Data are available from a 6-week randomized study comparing lithium plus quetiapine versus placebo plus quetiapine in adults with acute mania, which showed increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain in the group receiving lithium compared to the placebo group.

No clinically significant changes in the pharmacokinetics of sodium valproate and quetiapine were observed when administered concomitantly. In a retrospective study involving children and adolescents receiving sodium valproate, quetiapine, or a combination of these agents, increased incidence of leukopenia and neutropenia was observed in the group receiving both agents compared to groups receiving either agent alone.

Interaction studies with cardiovascular drugs have not been conducted.

Caution should be exercised when administering quetiapine concomitantly with medicinal products that affect electrolyte balance or prolong the QT interval.

False positive results in enzyme immunoassays for methadone and tricyclic antidepressants have been reported in patients taking quetiapine. It is recommended that questionable screening immunoassay results be confirmed using an appropriate chromatographic method.

Special precautions for use.

Since Ketylept® is indicated for the treatment of schizophrenia, bipolar disorder, and adjunctive treatment of depressive episodes in patients with MDD, the safety profile of the drug should be carefully considered with regard to the specific diagnosis and dose prescribed to the individual patient.

Children

Ketylept® is not recommended for use in children and adolescents under 18 years of age due to lack of data supporting its use in this age group. Clinical studies of quetiapine have shown that, in addition to the known safety profile established in adults (see section "Adverse reactions"), the frequency of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, and extrapyramidal symptoms), and one event not previously observed in adult clinical trials has been identified (elevated blood pressure). In addition, changes in thyroid function parameters have been observed in children and adolescents.

It should also be noted that the long-term impact of Ketylept® treatment on growth and sexual maturation has not been studied beyond 26 weeks. The long-term impact on cognitive and behavioral development is unknown.

It is known that in placebo-controlled clinical trials involving pediatric and adolescent patients, quetiapine treatment was associated with a higher incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section "Adverse reactions").

Suicide/suicidal thoughts or clinical worsening

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

Additionally, the potential risk of suicide-related events after abrupt discontinuation of quetiapine treatment should be considered due to the known disease-related risk factors.

Other psychiatric disorders for which Ketylept® is prescribed may also be associated with an increased risk of suicide-related events. Furthermore, these disorders may coexist with depressive episodes.

When treating patients with other psychiatric disorders, the same precautions should be taken as those applied when treating patients with major depressive episodes.

Patients with a history of suicide-related events or who exhibit significant levels of suicidal thinking prior to starting therapy are at higher risk of developing suicidal thoughts or attempting suicide and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age.

Close monitoring of patients, particularly those at high risk, should accompany pharmacological therapy, especially at the beginning of treatment and during subsequent dose adjustments. Patients (and caregivers) should be warned to monitor for clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical attention if symptoms occur.

In short-term placebo-controlled trials involving patients with major depressive episodes associated with bipolar disorders, a higher risk of suicide-related events was observed in young patients (under 25 years of age) treated with quetiapine compared to those treated with placebo (3.0% vs. 0%, respectively).

Extrapyramidal symptoms

In placebo-controlled trials, quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients receiving treatment for major depressive episodes associated with bipolar disorder and major depressive disorder (see section "Adverse reactions").

Quetiapine use has been associated with the development of akathisia, characterized by subjectively unpleasant or distressing restlessness and a compelling need to move, often accompanied by an inability to sit or stand still. These events are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may worsen their condition.

Tardive dyskinesia

If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing Ketylept®. Symptoms of tardive dyskinesia may worsen or even emerge after discontinuation of therapy (see section "Adverse reactions").

Drowsiness and dizziness

Treatment with quetiapine is associated with drowsiness and similar symptoms such as sedation (see section "Adverse effects"). In clinical trials involving patients with bipolar depression, these symptoms typically occurred within the first 3 days of treatment and were mostly mild to moderate in intensity. For patients with bipolar depression and patients with depressive episodes in MDD who experience drowsiness, monitoring may be required for 2 weeks after onset of drowsiness or until symptoms resolve, or consideration may be given to discontinuing treatment.

Orthostatic hypotension

Quetiapine treatment has been associated with orthostatic hypotension and accompanying dizziness in some patients (see section "Adverse reactions"), which, similar to drowsiness, usually occur during the dose titration period. These events may contribute to an increased frequency of accidental injuries (falls), particularly in elderly patients. Therefore, patients should be advised to exercise caution until they become accustomed to the possible effects of the drug.

Sleep apnea syndrome

Cases of sleep apnea syndrome have been reported in patients taking quetiapine; therefore, Ketylept® should be used with caution in patients with overweight/obesity, male patients, and patients receiving concomitant antidepressant therapy.

Cardiovascular disorders

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

Quetiapine may cause orthostatic hypotension, particularly at the beginning of dose titration; therefore, dose reduction or a longer titration period may be necessary in such cases.

Cardiomyopathy and myocarditis

Cases of cardiomyopathy and myocarditis have been reported in clinical trials and during post-marketing surveillance (see section "Adverse reactions"). If cardiomyopathy or myocarditis is suspected in a patient, discontinuation of quetiapine treatment should be considered.

Seizures

No difference in seizure frequency was observed between patients receiving quetiapine and those in the placebo group during clinical trials. There are no data on seizure frequency in patients with a history of epilepsy. As with other antipsychotic drugs, quetiapine should be prescribed with caution for the treatment of patients with a history of epileptic seizures (see section "Adverse reactions").

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome may be associated with treatment with antipsychotics, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, Ketylept® should be discontinued and appropriate treatment initiated.

Serotonin syndrome

Concomitant use of Ketylept® with other serotonergic drugs, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome—a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic drugs is clinically justified, close monitoring of the patient is recommended, especially at the beginning of treatment and during dose escalation. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

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

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count <0.5×10⁹/L) was infrequently observed in quetiapine clinical trials. Agranulocytosis (severe neutropenia with infection) has been reported rarely in patients receiving quetiapine during clinical trials and in the post-marketing period (including cases with fatal outcomes). Most cases of severe neutropenia occurred within two months of starting quetiapine therapy. No clear dose relationship has been 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 low white blood cell (WBC) count and drug-induced neutropenia in history. However, some cases occurred in patients without pre-existing risk factors. It is recommended to discontinue quetiapine treatment if the neutrophil count in blood is <1.0×10⁹/L. Patients should be monitored for signs and symptoms of infection and neutrophil levels should be controlled (until they exceed <1.5×10⁹/L) (see section "Adverse reactions").

The possibility of developing neutropenia should be considered in patients with existing infection, despite the absence of risk factors, as well as in patients with fever of unknown origin, and appropriate clinical measures should be applied.

Patients should be advised to immediately report any signs/symptoms indicating agranulocytosis or infection (such as fever, weakness, lethargy, or sore throat) at any time during treatment with Ketylept®. Such patients require timely assessment of white blood cell count and absolute neutrophil count (ANC), especially in the absence of predisposing factors.

Anticholinergic (muscarinic) syndrome

Norquetiapine, the active metabolite of quetiapine, has moderate to high affinity for several subtypes of muscarinic receptors, which may explain the anticholinergic (muscarinic) syndrome. This may contribute to adverse reactions reflecting anticholinergic effects, particularly when quetiapine is used concomitantly with other drugs having anticholinergic effects, especially in overdose situations. Quetiapine should be used with caution in patients receiving medications with anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with urinary tract pathology (urinary retention), significant prostatic hypertrophy, intestinal obstruction, elevated intraocular pressure, or angle-closure glaucoma (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Pharmacodynamic properties", "Overdose").

Interactions

See also section "Interaction with other medicinal products and other forms of interaction".

Concomitant use of quetiapine with a strong hepatic enzyme inducer, such as carbamazepine or phenytoin, significantly reduces quetiapine plasma concentrations, which may compromise the effectiveness of quetiapine therapy. Treatment with Ketylept® in patients receiving a hepatic enzyme inducer may only be initiated if the physician considers that the benefit of using Ketylept® outweighs the risks of discontinuing the enzyme inducer. It is important that any changes in the use of the inducer occur gradually. If necessary, the inducer should be replaced with a non-inducer (e.g., sodium valproate).

Effect on body weight

Weight gain has been reported during quetiapine treatment and should be monitored and clinically managed when using antipsychotic drugs.

Hyperglycemia

Hyperglycemia and/or development or exacerbation of diabetes mellitus have occasionally been associated with ketoacidosis or coma, rarely reported, including several cases with fatal outcomes (see section "Adverse effects"). Several cases have been reported with prior weight gain, which may be a predisposing factor. Appropriate clinical monitoring should be performed according to existing guidelines for antipsychotic drugs. Patients treated with any antipsychotic drugs, including quetiapine, should be monitored for 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 continuously monitored.

Lipids

Elevations in triglycerides, LDL cholesterol, and total cholesterol, and decreases in HDL cholesterol have been observed in quetiapine clinical trials (see section "Adverse reactions"). Appropriate treatment should be initiated if lipid levels change.

Metabolic risk

Due to the identified risk of worsening metabolic profile, including changes in body weight, glucose levels (see "Hyperglycemia"), and blood lipids observed in clinical trials, metabolic parameters should be assessed at the beginning of treatment and changes in these parameters should be regularly monitored during the course of treatment. Worsening of these parameters should be corrected considering clinical appropriateness.

QT interval prolongation

In clinical trials and according to the Instructions for Medical Use, quetiapine did not cause sustained increases 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 disorders or patients with a family history of prolonged QT interval. Caution should also be exercised when prescribing quetiapine with other drugs known to prolong the QT interval or when used concomitantly with other antipsychotics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia (see section "Interaction with other medicinal products").

Cardiomyopathy and myocarditis

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

Severe cutaneous adverse reactions

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

Discontinuation of the drug

Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability have been described after abrupt discontinuation of quetiapine. Therefore, gradual discontinuation of the drug over a period of at least one to two weeks is recommended (see section "Adverse effects").

Elderly patients with Parkinson's disease (PD)/parkinsonism

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

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

In randomized placebo-controlled trials in patients with dementia, an approximately threefold increased risk of cardiovascular adverse events was observed with the use of some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or other patient populations. Ketylept® should be used with caution in patients with risk factors for stroke.

According to meta-analyses of atypical antipsychotics, elderly patients with dementia-related psychosis represent a group at increased risk of fatal outcomes compared to placebo. However, data from two 10-week placebo-controlled trials of quetiapine in similar populations (n=710, age 83 years, range 56–99 years) showed a mortality rate of 5.5% in patients treated with quetiapine compared to 3.2% in the placebo group. The causes of death during the trials were varied and expected for this patient population. These data did not establish a causal relationship between quetiapine treatment and mortality in patients with dementia.

Dysphagia

Dysphagia has been reported with quetiapine use. Quetiapine should be used with caution in patients at risk of aspiration pneumonia (see section "Adverse reactions").

Constipation and intestinal obstruction

Constipation is a risk factor for intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with quetiapine use (see section "Adverse reactions"). These reports include fatal cases in patients at higher risk of intestinal obstruction, including those receiving multiple drugs that reduce intestinal motility and/or drugs for which constipation-related adverse events may not have been previously reported.

Venous thromboembolism (VTE)

Cases of venous thromboembolism (VTE) have been reported during treatment with antipsychotics. Since patients receiving antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during quetiapine therapy, and preventive measures should be taken.

Pancreatitis

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

Additional information

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

Lactose

Ketylept® tablets contain lactose. This medicinal product should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Ketylept® 25 mg contains 4 mg of lactose monohydrate per tablet.

Ketylept® 100 mg contains 16 mg of lactose monohydrate per tablet.

Ketylept® 200 mg contains 32 mg of lactose monohydrate per tablet.

Misuse and abuse

Cases of misuse and abuse of the drug have been reported. Quetiapine should be prescribed with caution to patients with a history of alcohol or drug abuse.

Use during pregnancy or breastfeeding.

Pregnancy

First trimester

The safety and efficacy of quetiapine use for treating pregnant women have not been established. Currently, there is no evidence of negative effects from animal studies. The potential effect on fetal visual organs has not been studied. Based on information from several pregnancies during which quetiapine was used, neonatal withdrawal symptoms have been reported in newborns. Therefore, Ketylept® should be prescribed during pregnancy only if the expected benefit outweighs the potential risk. Neonates whose mothers took quetiapine during pregnancy have exhibited withdrawal symptoms.

Third trimester

Newborns whose mothers took antipsychotic drugs (including quetiapine) during the third trimester are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration after birth. The following adverse reactions have been observed: agitation, arterial hypertension, hypotension, tremor, drowsiness, respiratory disorders, or feeding difficulties. Therefore, newborns should be closely monitored.

Breastfeeding

Published reports indicate that quetiapine passes into human breast milk, although the extent of transfer is unknown. Women who are breastfeeding are advised to discontinue breastfeeding during quetiapine treatment.

Ability to affect reaction speed when driving or operating machinery.

Since the drug primarily acts on the central nervous system, quetiapine may negatively affect activities requiring mental alertness. Therefore, patients should not drive or operate machinery until their individual sensitivity to this effect has been determined.

Dosage and Administration.

Different dosing regimens exist for each indication. It is essential to ensure that the patient receives a dose appropriate for their condition. The dosage and duration of treatment are determined individually by the physician depending on the indication and severity of the disease. For oral use. Ketilept® may be taken independently of food intake. Tablets should be swallowed whole, without breaking, chewing, or crushing.

Adults

Treatment of Schizophrenia

Ketilept® should be taken twice daily. During the first 4 days of therapy, the daily dose is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg. Starting from Day 4, the dose should be increased until the desired clinical effect is achieved (within the range of 300 to 450 mg/day). Depending on clinical efficacy and tolerability, the daily dose of Ketilept® may range 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 Disorder

Ketilept® should be taken twice daily. The daily dose during the first 4 days of treatment is: Day 1 – 100 mg, Day 2 – 200 mg, Day 3 – 300 mg, Day 4 – 400 mg. Thereafter, the dose should be increased (but not by more than 200 mg daily) up to 800 mg/day, starting from Day 6 of treatment. Depending on clinical efficacy and tolerability, the dose may range from 200 to 800 mg/day. The usual effective dose is within the range of 400 to 800 mg/day. The maximum daily dose of Ketilept® for the treatment of manic episodes is 800 mg.

Treatment of Depressive Episodes Associated with Bipolar Disorder

Ketilept® should be administered once daily at bedtime. The total daily dose for the first four days of treatment is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3), and 300 mg (Day 4). The recommended daily dose is 300 mg. Clinical studies did not show additional benefit in the 600 mg group compared to the 300 mg group (see section "Pharmacological Properties"). The 600 mg dose may be effective for some patients. Doses above 300 mg should be prescribed only by a physician experienced in treating bipolar disorder. Clinical studies indicate that for some patients experiencing tolerability issues, the dose should be reduced to the minimum of 200 mg.

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

Prevention of Relapse in Patients with Bipolar Disorder

To prevent subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who have responded to Ketilept® during acute treatment should continue therapy with Ketilept® at the same prescribed dose taken at bedtime. The dose of Ketilept® may be adjusted within the range of 300 mg to 800 mg/day, depending on the individual patient's clinical response and tolerability (twice daily). It is important 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 during the initial phase of treatment and dose titration. A slower dose titration of Ketilept® may be required, 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 subjects compared to younger patients.

Safety and efficacy in patients over 65 years of age with depressive episodes in bipolar disorder have not been studied.

Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Hepatic Impairment

Quetiapine is extensively metabolized in the liver. Therefore, Ketilept® should be used with caution in patients with known hepatic impairment, especially during the initial dose titration period. Treatment of patients with hepatic impairment should be initiated at a dose of 25 mg/day. The dose may be increased by 25–50 mg/day daily until an effective dose is reached, depending on the individual patient's clinical response and tolerability.

Children

Ketilept® is not recommended for use in children due to the lack of data supporting its use in this age group.

Overdose.

Symptoms

Clinical data on quetiapine overdose are limited. Manifestations and symptoms of overdose were due to the potentiation of known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, and hypotension. Overdose may lead to QT interval prolongation, seizures, epileptic status, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma, and fatal outcome. Patients with pre-existing severe cardiovascular disease may have an increased risk of overdose effects (see section "Special Warnings").

Treatment

There is no specific antidote for quetiapine. In cases of significant intoxication, appropriate measures and intensive therapy should be considered, including restoration and maintenance of airway patency, ensuring adequate oxygenation and ventilation, and monitoring and supporting cardiovascular function. Published reports describe cases of reversal of serious CNS reactions, including coma and delirium, with intravenous physostigmine (1–2 mg) administered under continuous ECG monitoring. Physostigmine should not be used if arrhythmia, any degree of heart block, or QRS complex widening is present.

In cases of persistent hypotension due to quetiapine overdose, appropriate measures should be taken, such as intravenous fluid administration and/or sympathomimetics (epinephrine and dopamine should be avoided, as stimulation of beta-adrenergic receptors may worsen hypotension under conditions of alpha-adrenergic receptor blockade caused by quetiapine).

Since prevention of absorption has not been studied in overdose, gastric lavage should be considered and, if possible, performed within 1 hour after drug ingestion (after intubation if the patient is unconscious), but no later than 1 hour after drug intake, along with activated charcoal combined with a laxative.

Careful medical monitoring and observation should continue until full recovery of the patient.

Adverse reactions

The most commonly reported adverse reactions with quetiapine (≥ 10%) are: somnolence, dizziness, dry mouth, headache, withdrawal symptoms (upon discontinuation of the drug), increased serum triglyceride levels, increased total cholesterol levels (particularly LDL-cholesterol), decreased HDL-cholesterol levels, weight gain, decreased hemoglobin, and extrapyramidal symptoms.

As with other antipsychotic medicinal products, cases of loss of consciousness, neuroleptic malignant syndrome, leukopenia, neutropenia, and peripheral edema have been reported during treatment with quetiapine.

The frequency of adverse reactions with quetiapine is listed below (Table 1), according to the following classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).

Table 1

1. See section "Special precautions".

2. Drowsiness may occur, usually during the first 2 weeks of treatment, and usually resolves with continued use of quetiapine.

3. Asymptomatic increases (shift from normal to >3 ULN at any time) in transaminase levels (ALT, AST) or gamma-GT (glutamyl transferase) were observed in some patients treated with quetiapine. These increases were generally reversible with continued quetiapine treatment.

4. Like other antipsychotic medicinal products that block alpha1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, particularly during the initial dose titration period (see section "Special precautions").

5. The frequency of these adverse reactions was assessed only from post-marketing data on quetiapine use in the immediate-release formulation.

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

7. An increased incidence of dysphagia with quetiapine compared to placebo was observed only in clinical trials of bipolar depression.

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

9. Withdrawal symptoms most commonly observed in short-term placebo-controlled monotherapy clinical trials, where withdrawal symptoms were assessed, included insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions decreased significantly within one week after discontinuation of treatment.

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

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

12. See text below.

13. Platelet count ≤100×10⁹/L at least once.

14. According to clinical trial reports of adverse reactions, elevated blood creatine phosphokinase levels are not associated with neuroleptic malignant syndrome.

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

16. May lead to falls.

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

18. Number of patients with change in QTc interval duration from <450 msec to ≥450 msec with an increase of ≥30 msec. In placebo-controlled studies of quetiapine, mean change and number of patients with shift to clinically significant levels were similar in quetiapine and placebo groups.

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

20. Suicidal ideation and suicidal behavior have been reported during therapy with quetiapine or immediately after discontinuation of treatment (see sections "Special precautions" and "Pharmacological properties").

21. See section "Pharmacological properties".

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

23. These events often occurred in the context of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disease.

24. Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for total T4, free T4, total T3, and free T3 was <0.8× ULN (pmol/L), and deviation for TSH was >5 mIU/L at any time.

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

26. Based on deviations in neutrophil count from ≥1.5×10⁹/L at baseline to <0.5×10⁹/L at any time during treatment and based on occurrence of patients with severe neutropenia (<0.5×10⁹/L) and infection across all clinical trials of quetiapine.

27. Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for eosinophils was >1×10⁹ cells/L at any time.

28. Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for leukocytes was ≤3×10⁹ cells/L at any time.

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

30. During clinical trials, some patients exhibited worsening of more than one metabolic factor affecting body weight, blood glucose, and lipids (see section "Special precautions").

31. See section "Use in pregnancy or lactation".

32. May occur during or shortly after initiation of therapy and may be associated with hypotension and/or syncope. Frequency is based on reports of bradycardia and related events observed in all clinical trials of quetiapine.

33. Based on one retrospective, non-randomized epidemiological study.

Cases of prolonged QT interval, ventricular arrhythmia, sudden unexplained death, cardiac arrest, and torsade de pointes arrhythmia have been reported with the use of neuroleptic medicinal products and are considered class-specific for this group of drugs.

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

Children.

The adverse reactions listed above observed in adults also occur in pediatric and adolescent patients (10–17 years of age).

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

Table 2 below summarizes adverse reactions with higher incidence in pediatric and adolescent patients (10–17 years of age) or those not observed in adult patients.

Adverse reactions are listed according to frequency of occurrence using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000).

Table 2

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

2 Based on deviations above clinically significant values (according to National Institute of Health criteria) or increase of >20 mm Hg for systolic or >10 mm Hg for diastolic blood pressure at any time in two short-term (3–6 weeks) placebo-controlled studies in children and adolescents.

3 Note: 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 section "Pharmacodynamics".

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 tablets in a blister; 3 or 6 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. EGIS Pharmaceuticals Ltd., Hungary.

Manufacturer's address and location of its business operations.

118-120 Bekenyfelti Street, Budapest 1165, Hungary.