Kvetiksol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Kvetixol (Quetixol)

Composition:

Active substance: quetiapine;

One film-coated tablet contains 25 mg or 100 mg or 200 mg of quetiapine fumarate equivalent to quetiapine;

Excipients: microcrystalline cellulose; povidone K29-32; calcium hydrogen phosphate dihydrate; sodium starch glycolate (type A); lactose monohydrate; magnesium stearate;

for 25 mg: coating Opadry II Pink 33G34594 (hypromellose 6cP; titanium dioxide (E 171); lactose monohydrate; polyethylene glycol 3350; triacetin; yellow iron oxide (E 172); red iron oxide (E 172));

for 100 mg: coating Opadry II Yellow 33G32578 (hypromellose 6cP; titanium dioxide (E 171); lactose monohydrate; polyethylene glycol 3350; triacetin; yellow iron oxide (E 172));

for 200 mg: coating Opadry II White 33G28435 (hypromellose 6cP; titanium dioxide (E 171); lactose monohydrate; polyethylene glycol 3350; triacetin).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

film-coated tablets 25 mg: light orange, round, biconvex, with inscription "Q" on one side;

film-coated tablets 100 mg: yellow, round, biconvex, with inscription "Q" on one side;

film-coated tablets 200 mg: white, oval, biconvex, with inscription "Q" on one side.

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05A H04.

Pharmacological properties.

Mechanism of action.

Quetiapine is an atypical antipsychotic agent. Quetiapine and its active metabolite norquetiapine interact with various types of neurotransmitter receptors. Quetiapine and norquetiapine have high selectivity for serotonin (5-HT2) receptors and dopamine D1 and D2 receptors in the brain. This combination of receptor antagonism, with greater selectivity for 5-HT2 receptors relative to D2 receptors, is considered responsible for the clinical antipsychotic effects of the drug Kvetiksol and its low propensity for extrapyramidal side effects compared to typical antipsychotic agents. Quetiapine and norquetiapine also have high affinity for histamine and α1-adrenergic receptors, but lower affinity for α2-adrenergic receptors and serotonin 5-HT1A receptors.

Quetiapine has no affinity for cholinergic muscarinic receptors or benzodiazepine receptors, whereas norquetiapine 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 5-HT1A receptors, may contribute to the therapeutic efficacy of Kvetiksol as an antidepressant.

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 blockade of D2 receptors.

Preclinical studies evaluating the potential for extrapyramidal symptoms have shown that quetiapine has an atypical activity profile and differs from standard antipsychotic agents. With prolonged administration, quetiapine does not lead to excessive sensitivity of dopamine D2 receptors. Quetiapine causes only mild catalepsy at doses effective for blocking dopamine D2 receptors.

After 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 dose-dependent reduction in thyroid hormone levels.

Available data from placebo-controlled trials involving elderly patients with psychosis associated with dementia show that the incidence of cardiovascular adverse events per 100 patient-years in the quetiapine group was no higher than in patients receiving placebo.

Cataraсt

Data from a clinical study assessing the cataractogenic potential of quetiapine (200–800 mg/day) compared to risperidone (2–8 mg/day) in patients with schizophrenia or schizoaffective disorder showed that the percentage of patients with increased lens opacity was no higher in the quetiapine group (4%) than in the risperidone group (10%) after at least 21 months of treatment.

Pharmacokinetics.

Absorption.

Quetiapine is well absorbed after oral administration and undergoes extensive metabolism. Administration with food does not result in a significant change in quetiapine bioavailability.

At steady state, the maximum molar concentration of the active metabolite norquetiapine is approximately 35% of the concentration of quetiapine. The pharmacokinetics of quetiapine and norquetiapine within the approved dose range are linear.

Distribution.

Approximately 83% of quetiapine is protein-bound in plasma.

Metabolism.

Quetiapine is extensively metabolized in the liver. Studies using radiolabeled quetiapine have shown that less than 5% of the drug is excreted unchanged in urine or feces. In vitro studies have established that CYP3A4 is the primary cytochrome P450 enzyme responsible for quetiapine metabolism. The formation and elimination of norquetiapine occur predominantly via the CYP3A4 isoenzyme.

Approximately 73% of the radiolabeled dose is excreted in urine and 21% in feces.

Quetiapine and some of its metabolites (including norquetiapine) exhibit weak inhibitory effects in vitro on the cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4.

Inhibition of CYP isoenzymes in vitro occurred only at concentrations 5–50 times higher than those achieved with human doses ranging from 300 mg to 800 mg per day. Based on these in vitro results, it is unlikely that concomitant administration of quetiapine with other active substances will result in clinically significant inhibition of the metabolism of other drugs mediated by cytochrome P450.

Elimination.

The elimination half-life of quetiapine and norquetiapine is approximately 7 hours and 12 hours, respectively. The mean molar fraction of free quetiapine and the active metabolite N-desalkylquetiapine excreted in urine is < 5% of the administered dose.

Special populations.

Gender.

The pharmacokinetics of quetiapine in women and men are not different.

Elderly patients.

The average clearance of quetiapine in elderly patients is 30–50% lower than in 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), the average plasma clearance of quetiapine is reduced by approximately 25%, but individual clearance values remain within the range observed in healthy individuals.

Patients with hepatic impairment.

In patients with liver disease (compensated alcoholic cirrhosis), the average 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:

• for the treatment of moderate to severe manic episodes associated with bipolar disorders;
• for the treatment of major depressive episodes associated with bipolar disorders;
• for the prevention of recurrence 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 interactions").

Interaction with other medicinal products and other forms of interactions.

Since quetiapine primarily acts on the central nervous system (CNS), Quetisox should be used with caution in combination with other agents having similar effects and with alcohol.

Quetiapine should be used with caution together 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—is increased (see section "Special precautions for use").

The pharmacokinetics of lithium were not altered when administered concomitantly with quetiapine. Data from a randomized 6-week trial comparing lithium plus quetiapine versus placebo plus quetiapine in adult patients with acute mania showed an increased frequency of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain in the lithium add-on group compared to the placebo add-on 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, an increased incidence of leukopenia and neutropenia was observed in the group receiving both agents compared to groups receiving either agent alone.

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

In a multiple-dose study assessing the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a known hepatic enzyme inducer), concomitant use of carbamazepine significantly increased the clearance of quetiapine. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to an average of 13% of exposure observed with quetiapine alone, although a greater effect was observed in some patients. Due to this interaction, plasma concentrations may be reduced; therefore, dose adjustment of Quetisox should be considered for each patient based on clinical response. Concomitant use of Quetisox with phenytoin (another microsomal enzyme inducer) leads to an increase in quetiapine clearance by up to 450%. For patients taking a hepatic enzyme inducer, initiation of quetiapine therapy should only be considered if the physician determines that the benefit of quetiapine outweighs the risks associated with discontinuing the enzyme inducer. It is important that any changes in the administration of the inducer be made gradually. The dose of quetiapine may need to be reduced when phenytoin, carbamazepine, or other hepatic enzyme inducers are discontinued or replaced by an agent without inducing effects on hepatic microsomal enzymes (e.g., sodium valproate).

CYP3A4 is the key enzyme involved in the cytochrome P450-mediated metabolism of quetiapine. In interaction studies in healthy volunteers, concomitant administration of quetiapine (25 mg) with ketoconazole (a CYP3A4 inhibitor) resulted in a 5- to 8-fold increase in quetiapine AUC. Therefore, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. Consumption of grapefruit juice should also be avoided during treatment with quetiapine.

The pharmacokinetics of quetiapine were not altered after concomitant administration with cimetidine, a known inhibitor of the P450 enzyme.

The pharmacokinetics of quetiapine were only minimally affected after concomitant administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).

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

Interaction studies with cardiovascular medicinal products have not been conducted.

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

In patients taking quetiapine, false positive results in enzyme immunoassays for methadone and tricyclic antidepressants have been reported. Suspicious screening immunoassay results should be confirmed using an appropriate chromatographic method.

Special precautions for use.

Since quetiapine is indicated for the treatment of several conditions, the safety profile of the drug should be carefully considered in relation to the specific diagnosis established for the patient and the dose being administered.

Children.

Quetiapine is not recommended for use in children and adolescents under 18 years of age due to the lack of data on use of the drug 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, vomiting, rhinitis, syncope), or may have different complications in children and adolescents (extrapyramidal symptoms and irritability). Additionally, increased blood pressure has been observed, which was not previously reported in studies involving adult patients. Furthermore, changes in thyroid function parameters have been observed in children.

It should also be noted that the long-term impact of quetiapine 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 during placebo-controlled clinical trials of quetiapine involving pediatric patients, treatment with quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania, and depression (see section *“*Adverse reactions”).

Suicide/suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until a significant remission is achieved. Since improvement may not occur during the first few 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 known risk factors associated with the condition being treated.

Other psychiatric disorders for which quetiapine is prescribed may also be associated with an increased risk of suicide-related events. Moreover, these disorders may coexist with depressive episodes. Therefore, the same precautions should be taken when treating other psychiatric disorders as when treating depressive episodes.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal thoughts prior to the start of treatment have a higher risk of suicidal thoughts or suicide attempts and require careful monitoring during treatment. It is known that a meta-analysis of placebo-controlled clinical trials involving antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressant treatment compared to placebo in patients under 25 years of age.

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

In short-term placebo-controlled trials involving patients with severe depressive episodes in bipolar disorders, an increased 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).

Metabolic risk.

Due to changes observed during clinical trials regarding body weight, blood glucose (see hyperglycemia), and lipid parameters, there is a possibility of worsening the metabolic risk profile in individual patients, which may require appropriate treatment (see section "Adverse reactions").

Orthostatic hypotension.

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

Kvetiksol should be used with caution in patients with established cardiovascular and cerebrovascular diseases or other conditions that may lead to hypotension. Quetiapine may cause orthostatic hypotension, especially during the initial period of gradual dose escalation. If this occurs, the dose or rate of dose escalation should be reduced. A slow titration regimen may be considered for patients with cardiovascular diseases.

Seizures.

There was no difference in the frequency of seizures between patients taking quetiapine and those taking placebo. There are no data on the frequency of seizures in patients with a history of seizure disorders. As with treatment with other antipsychotic drugs, caution is recommended when prescribing the drug to patients with a history of seizures.

Extrapyramidal symptoms.

It is known that in placebo-controlled trials, quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in adult patients receiving treatment for major depressive episodes associated with bipolar disorder (see section "Adverse reactions"). The use of quetiapine has been associated with the development of akathisia, characterized by subjectively unpleasant or distressing restlessness and a need to move, often accompanied by an inability to sit or stand still. These phenomena are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may be harmful.

Tardive dyskinesia.

If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing the drug.

Symptoms of tardive dyskinesia may worsen and may even occur after discontinuation of therapy (see section "Adverse reactions").

Somnolence and dizziness.

Treatment with quetiapine is associated with somnolence and similar symptoms such as sedation (see section "Adverse reactions"). During clinical trials, such symptoms in patients with bipolar depression usually occurred within the first 3 days of treatment and were predominantly mild to moderate in intensity. For patients with bipolar depression who experience somnolence, monitoring may be necessary for 2 weeks after the onset of somnolence or until symptoms resolve, or it may be necessary to consider discontinuing treatment.

Sleep apnea syndrome.

Cases of sleep apnea syndrome have been reported in patients taking quetiapine; therefore, quetiapine should be used with caution in patients with a history of sleep apnea syndrome or those at risk of its development, such as patients with excess body weight/obesity, male patients, and patients receiving concomitant therapy with CNS depressant drugs.

Malignant neuroleptic syndrome.

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

Serotonin syndrome.

Concomitant use of the medicinal product Kvetiksol and other serotonergic medicinal products, 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 types of interactions").

If concomitant treatment with other serotonergic medicinal products is clinically justified, careful 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.

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

Severe neutropenia and agranulocytosis.

It is known that severe neutropenia (neutrophil count < 0.5×10⁹/L) has occurred during quetiapine studies. Most cases of severe neutropenia occurred within several months after the start of quetiapine therapy. There is no apparent dose dependency. In the post-marketing period, cases of severe neutropenia with fatal outcomes have been reported. Possible risk factors for neutropenia include previously observed low white blood cell count and a history of drug-induced neutropenia. Cases of agranulocytosis have occurred in patients without pre-existing risk factors. The use of quetiapine in patients with neutrophil count < 1.0 × 10⁹/L should be discontinued. Patients should be monitored for signs of infection, and neutrophil count should be monitored (until it exceeds 1.5 × 10⁹/L).

The possibility of developing neutropenia should be considered in patients with infection, especially in the absence of obvious predisposing factor(s), and in patients with unexplained fever, and appropriate clinical measures should be taken. Patients should be advised to immediately report symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during quetiapine treatment, and timely monitoring of white blood cell count and absolute neutrophil count should be performed, especially in the absence of triggering factors.

Anticholinergic (muscarinic) effects.

Norquetiapine, the active metabolite of quetiapine, has moderate or high affinity for several subtypes of muscarinic receptors. This contributes to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used at recommended doses, when quetiapine is used concomitantly with other drugs having anticholinergic effects, and in cases of overdose. Quetiapine should be used with caution in patients receiving drugs with anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with urinary retention, significant prostatic hyperplasia, intestinal obstruction, elevated intraocular pressure, or closed-angle glaucoma present at the time of treatment or in medical history (see sections "Interaction with other medicinal products and other types of interactions", "Adverse reactions", "Pharmacodynamic properties", "Overdose").

Abrupt discontinuation of the drug.

After abrupt discontinuation of high-dose antipsychotic treatment, acute withdrawal symptoms such as nausea, vomiting, headache, diarrhea, dizziness, irritability, and insomnia have very rarely been described. Relapses of psychotic symptoms and the emergence of disorders such as involuntary movements (e.g., akathisia, dystonia, and dyskinesia) have been reported. Therefore, gradual discontinuation of the drug over a period of at least 1 to 2 weeks is recommended.

Interactions.

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

Concomitant use of quetiapine with potent inducers of hepatic enzymes, such as carbamazepine or phenytoin, significantly reduces quetiapine plasma concentration, which may reduce its efficacy. Treatment with Kvetiksol in patients receiving a hepatic enzyme inducer may be initiated only if the physician considers the benefit of using the drug to outweigh the risks of discontinuing the hepatic enzyme inducer. It is important that any changes in the use of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate).

Effect on body weight.

During treatment with quetiapine, weight gain has been reported, which should be monitored and managed appropriately according to recommendations for the use of antipsychotics.

Hyperglycemia.

In rare cases, hyperglycemia and/or the development or exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, including several cases with fatal outcomes, have been reported (see section "Adverse reactions"). In some cases, these events occurred in patients with increased body weight, which could be a predisposing factor. Adequate clinical monitoring according to appropriate recommendations for the use of antipsychotic agents is recommended. Patients receiving any antipsychotic agent, including quetiapine, should be monitored for possible signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for developing diabetes mellitus should be regularly monitored for possible worsening of glucose control. Body weight should be monitored regularly.

Lipids.

Cases of increased triglycerides, low-density lipoproteins, and total cholesterol, as well as decreased high-density lipoproteins, have been described (see section "Adverse reactions"). Treatment according to clinical indications is required when lipid levels change.

QT interval prolongation.

During clinical trials and use of quetiapine according to instructions, no consistent increase in the absolute value of the QT interval was observed. In the post-marketing period, QT interval prolongation has been reported with therapeutic doses (see section "Adverse reactions") and in cases of overdose (see section "Overdose"). As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases or patients with a family history of prolonged QT interval. When prescribing quetiapine concomitantly with drugs that prolong the QT interval or other neuroleptics, caution is required (see section *“*Interaction with other medicinal products and other types of interactions”), especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.

Cardiomyopathy and myocarditis.

Cases of cardiomyopathy and myocarditis have been reported during clinical trials and the post-marketing period with quetiapine use (see section "Adverse reactions"). In patients suspected of cardiomyopathy or myocarditis, discontinuation of quetiapine treatment should be considered.

Elderly patients with psychosis associated with dementia.

Kvetiksol is not approved for the treatment of psychosis associated with dementia.

In patients with dementia, use of some atypical antipsychotics has been associated with an almost threefold increased risk of adverse cerebrovascular events. The mechanism of this increased risk is unknown. Increased risk cannot be excluded for other antipsychotics or for other patient categories. Quetiapine should be used with caution in patients with risk factors for stroke.

According to a meta-analysis of atypical antipsychotics, elderly patients suffering from psychosis associated with dementia represent a group at increased risk of fatal outcome compared to placebo. However, data from two 10-week placebo-controlled studies of quetiapine use in similar populations (mean 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 studies were varied and expected for this patient population.

Elderly patients with Parkinson's disease/parkinsonism.

A retrospective population-level study investigating the use of quetiapine for the treatment of patients with major depressive disorders showed an increased risk of fatal outcome in patients aged 65 years and older during quetiapine use. This association was not observed when patients with Parkinson's disease were excluded from the study. Caution is required when prescribing quetiapine to elderly patients with Parkinson's disease.

Dysphagia.

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

Constipation and intestinal obstruction.

Constipation is a risk factor for the development of intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with the use of quetiapine (see section "Adverse reactions"). These reports include reports of fatal cases in patients who have a higher risk of developing intestinal obstruction, including those receiving multiple drugs that reduce intestinal peristalsis and/or those who may not report symptoms of constipation. Patients with intestinal obstruction/ileus should be monitored through careful monitoring and provision of emergency medical care.

Hepatic effects.

If jaundice occurs, quetiapine should be discontinued.

Venous thromboembolism.

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

Pancreatitis.

Cases of pancreatitis have been reported in clinical trials and during the post-marketing period. Among marketing reports, many patients, although not all, had factors known to be associated with pancreatitis, such as elevated triglyceride levels, gallstones, and alcohol consumption.

Additional information.

Data on the use of quetiapine in combination with divalproex or lithium in 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.

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 and drug abuse.

Lactose.

The drug contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

The safety and efficacy of the drug during pregnancy have not been established; therefore, the drug Kvetiksol should be prescribed only when the expected benefit to the mother outweighs the potential risk to the fetus.

The use of antipsychotic drugs (including quetiapine) during the third trimester of pregnancy may lead to adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after delivery. Reports have included agitation, arterial hypertension, arterial hypotension, somnolence, respiratory distress syndrome, or feeding disorders. Therefore, newborns should be closely monitored.

Period of breastfeeding

The extent of quetiapine excretion in breast milk is not determined; therefore, breastfeeding should be discontinued during treatment with the drug.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Different dosing regimens exist for each indication. It is essential to ensure that the patient receives a dosage appropriate for their condition. Quetixol can be taken independently of food intake.

Adults

Treatment of Schizophrenia

Quetiapine should be taken twice daily.

The total daily dose during 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 Day 4 onwards, the dose should be titrated within the usual effective dose range of 300–450 mg per day. Depending on clinical efficacy and individual tolerability, the dose may be adjusted within the range of 150–750 mg per day.

Treatment of Moderate to Severe Manic Episodes Associated with Bipolar Disorder

Quetiapine should be taken twice daily.

The total daily dose during the first four days of therapy is 100 mg (Day 1), 200 mg (Day 2), 300 mg (Day 3), and 400 mg (Day 4). Further dose escalation up to 800 mg/day by Day 6 should occur gradually, increasing the dose by no more than 200 mg/day.

Depending on clinical efficacy and tolerability, the dose may range from 200 mg to 800 mg per day. The usual effective dose is within the range of 400 mg to 800 mg per day.

Treatment of Major Depressive Episodes Associated with Bipolar Disorders

Quetixol 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 have shown no additional benefit with a 600 mg dose compared to 300 mg. A dose of 600 mg may be effective in some patients. Doses above 300 mg should be prescribed only by physicians experienced in treating bipolar disorder. Clinical trial data suggest that for some patients experiencing tolerability issues, the dose should be reduced to the minimum of 200 mg.

For Prevention of Relapse in Patients with Bipolar Disorders

To prevent subsequent manic, mixed, or depressive episodes in patients with bipolar disorder who have responded to Quetixol during acute treatment, continuation therapy with Quetixol at the same prescribed dose is recommended. The dose of Quetixol may be adjusted within the range of 300–800 mg/day, depending on the individual patient's clinical response and tolerability (administered twice daily). It is important to use the lowest effective doses for maintenance therapy.

Elderly Patients

Like other antipsychotic agents, Quetixol should be used with caution in elderly patients, particularly during initial treatment and dose titration. Slower dose titration may be required, and the daily therapeutic dose may be lower than that used in younger patients, depending on the individual patient's clinical response and tolerability. 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

No dose adjustment is necessary for patients with renal impairment.

Hepatic Impairment

Quetiapine is extensively metabolized in the liver. Therefore, Quetixol should be used with caution in patients with known hepatic impairment, especially during the initial dose titration period. Treatment in patients with hepatic impairment should begin 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

The safety and efficacy of the drug in children (under 18 years of age) have not been established; therefore, the drug should not be used in pediatric practice.

Overdose

Symptoms

Overall, symptoms and manifestations reported in overdose cases were consequences of the enhanced known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, hypotension, and anticholinergic effects.

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.

Treatment

There is no specific antidote for quetiapine. In cases of severe intoxication, appropriate supportive measures should be considered, and intensive care procedures are recommended, including restoration and maintenance of airway patency, adequate oxygenation and ventilation, and monitoring and support of cardiovascular function.

Based on published literature, patients with delirium, agitation, and anticholinergic syndrome may be treated with physostigmine (1–2 mg) administered under continuous ECG monitoring. However, this treatment is not recommended as standard due to the potential adverse effects of physostigmine on cardiac conduction. Physostigmine should only be used if no ECG abnormalities are present. Physostigmine must not be administered in cases of arrhythmias, any degree of heart block, or QRS complex widening.

Persistent hypotension following quetiapine overdose should be managed with appropriate measures such as intravenous fluid administration and/or sympathomimetics.

Adrenaline (epinephrine) and dopamine should be avoided, as beta-stimulation may worsen hypotension in the presence of alpha-blockade induced by quetiapine.

In cases of severe overdose, gastric lavage (after intubation if the patient is unconscious) may be performed, but no later than 1 hour after drug ingestion. Activated charcoal together with a laxative may also be administered.

Close medical monitoring and observation should continue until full recovery.

Adverse Reactions

The most commonly reported adverse reactions during quetiapine treatment (≥10%) are: somnolence, dizziness, dry mouth, headache, withdrawal syndrome, increased serum triglycerides, increased total serum cholesterol (predominantly LDL cholesterol), decreased HDL cholesterol, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.

The frequency of adverse reactions is defined as follows: 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); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: very common – decreased hemoglobin²²; common – leukopenia¹,²⁸, decreased neutrophil count, increased eosinophil levels²⁷; uncommon – neutropenia¹, thrombocytopenia, anemia, decreased platelet count¹³; rare – agranulocytosis²⁶.

Immune system disorders: uncommon – hypersensitivity (including skin allergic reactions); very rare – anaphylactic reaction⁵.

Endocrine system disorders: common – hyperprolactinemia¹⁵, decreased total T4²⁴, decreased free T4²⁴, decreased total T3²⁴, increased TSH²⁴; uncommon – decreased free T3²⁵, hypothyroidism²¹; very rare – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: very common – increased serum triglycerides¹⁰,³⁰, increased total cholesterol (especially LDL cholesterol)¹¹,³⁰, decreased high-density lipoprotein (HDL) cholesterol¹⁷,³⁰, weight gain⁸,³⁰; common – increased appetite, increased blood glucose levels reaching values characteristic of hyperglycemia⁶,³⁰; uncommon – hyponatremia¹⁹, diabetes mellitus¹,⁵, worsening of diabetes; rare – metabolic syndrome²⁹.

Psychiatric disorders: common – abnormal dreams, nightmares, suicidal thoughts and behavior²⁰; rare – sleepwalking and related events such as sleep talking and sleep-related eating disorders.

Nervous system disorders: very common – dizziness⁴,¹⁶, somnolence²,¹⁶, headache, extrapyramidal symptoms¹,²¹; common – dysarthria; uncommon – seizures¹, restless legs syndrome, tardive dyskinesia¹,⁵, loss of consciousness⁴,¹⁶.

Cardiac disorders: common – tachycardia⁴, palpitations²³; uncommon – QT interval prolongation¹,¹²,¹⁸, bradycardia³²; frequency not known – cardiomyopathy and myocarditis.

Vascular disorders: common – orthostatic hypotension⁴,¹⁶; rare – venous thromboembolism¹; frequency not known – stroke³³.

Eye disorders: common – blurred vision.

Respiratory, thoracic and mediastinal disorders: common – dyspnea²³; uncommon – rhinitis.

Gastrointestinal disorders: very common – dry mouth; common – constipation, dyspepsia, vomiting²⁵; uncommon – dysphagia⁷; rare – pancreatitis¹, intestinal obstruction/ileus.

Hepatobiliary disorders: common – increased transaminase levels (alanine aminotransferase³, gamma-glutamyl transferase³); uncommon – increased aspartate aminotransferase levels³; rare – jaundice⁵, hepatitis.

Skin and subcutaneous tissue disorders: very rare – angioedema⁵, Stevens-Johnson syndrome⁵; frequency not known – toxic epidermal necrolysis, erythema multiforme, DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), frequency not known – cutaneous vasculitis.

Musculoskeletal and connective tissue disorders: very rare – rhabdomyolysis.

Renal and urinary disorders: uncommon – urinary retention.

Pregnancy, puerperium and perinatal conditions: frequency not known – drug withdrawal syndrome in newborns³¹.

Reproductive system and breast disorders: uncommon – sexual dysfunction; rare – priapism, galactorrhea, breast enlargement, menstrual cycle disturbances.

General disorders: very common – withdrawal symptoms¹,⁹; common – mild asthenia, peripheral edema, irritability, pyrexia; rare – neuroleptic malignant syndrome¹, hypothermia.

Investigations: rare – increased creatine phosphokinase levels¹⁴.

Notes:

1 – see section "Special precautions for use";

2 – somnolence may occur during the first two weeks of treatment and usually resolves with continued quetiapine therapy;

3 – asymptomatic increases (shift from baseline to >3×ULN at any time) in transaminase levels (ALT, AST) or gamma-GT (gamma-glutamyl transferase) have been observed in some patients receiving quetiapine. These increases were usually reversible with continued treatment.

4 – like other antipsychotics blocking α1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension, accompanied by dizziness, tachycardia, and in some patients, syncope, particularly during initial dose titration (see section "Special precautions for use").

5 – frequency estimates for these adverse reactions were based solely on post-marketing data.

6 – fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or postprandial blood glucose ≥200 mg/dL (≥11.1 mmol/L) on at least one occasion.

7 – 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 from baseline. Occurs predominantly during the first weeks of therapy in adults.

9 – withdrawal symptoms most commonly observed in short-term placebo-controlled monotherapy trials, which assessed withdrawal symptoms: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions significantly decreased one week after discontinuation.

10 – triglyceride level ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years) or ≥150 mg/dL (≥1.694 mmol/L) (patients <18 years) on at least one occasion.

11 – cholesterol level ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years) or ≥200 mg/dL (≥5.172 mmol/L) (patients <18 years) on at least one occasion.

Increase in LDL cholesterol ≥30 mg/dL (≥0.769 mmol/L) occurred very commonly. The mean value among patients with such increase was 41.7 mg/dL (1.07 mmol/L).

12 – see text below.

13 – platelets ≤100×10⁹/L on at least one occasion.

14 – according to adverse reaction reports from clinical trials, increased blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.

15 – prolactin levels (patients >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 from <450 msec to ≥450 msec with increase ≥30 msec. In placebo-controlled quetiapine trials, 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 once.

20 – cases of suicidal thoughts and suicidal behavior were reported during quetiapine therapy or immediately after discontinuation (see sections "Special precautions for use" and "Pharmacological properties").

21 – see section "Pharmacological properties".

22 – hemoglobin decrease 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 quetiapine-treated patients across all studies including open-label trials. 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 pre-existing cardiac/respiratory conditions.

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×LLN (pmol/L), and deviation for TSH was >5 mU/L at any time.

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

26 – based on neutrophil level deviations from baseline ≥1.5×10⁹/L to <0.5×10⁹/L at any time during treatment and on patients with severe neutropenia (<0.5×10⁹/L) and infection across all quetiapine clinical trials (see section "Special precautions for use").

27 – based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Eosinophil deviation 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. Leukocyte deviation was ≤3×10⁹ cells/L at any time.

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

30 – during clinical trials, some patients experienced worsening of more than one metabolic parameter: body weight, blood glucose, and lipid levels (see section "Special precautions for use").

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 adverse reaction reports of bradycardia and related events observed in all quetiapine clinical trials.

33 – based on data from one retrospective non-randomized epidemiological study.

Cases of QT interval prolongation on ECG, ventricular arrhythmia, polymorphic ventricular tachycardia (torsade de pointes), sudden unexplained death, and cardiac arrest have been reported with the use of neuroleptics. These effects are considered class-specific.

Serious skin adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome with eosinophilia and systemic symptoms, have been reported and associated with quetiapine therapy.

Children. The adverse reactions listed above observed in adults also occur in children. The table below summarizes adverse reactions with higher incidence in this age group or not observed in adults.

Frequency of adverse reactions is defined as: 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).

Endocrine disorders: very common – increased prolactin levels¹.

Metabolism and nutrition disorders: very common – increased appetite.

Nervous system disorders: very common – extrapyramidal symptoms³,⁴; common – syncope.

Vascular disorders: very common – increased blood pressure².

Respiratory system disorders: common – rhinitis.

Gastrointestinal disorders: very common – vomiting.

General disorders: common – irritability³.

Notes:

1 – prolactin levels (patients <18 years): >20 µg/L (>869.56 pmol/L) in males; >26 µg/L (>1130.428 pmol/L) in females at any time. Less than 1% of patients had prolactin levels >100 µg/L.

2 – based on deviation above clinically significant thresholds (adapted from National Institutes of Health criteria) or increase >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time, according to data from short-term (3–6 weeks) placebo-controlled trials 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 "Pharmacological properties".

Shelf life. 3 years.

Storage conditions.

Store in original packaging at temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Actavis Ltd. / Actavis Ltd.

Manufacturer's address.

BLB015, BLB016, Bulebel Industrial Estate, Zejtun, ZTN3000, Malta / BLB015, BLB016, Bulebel Industrial Estate, Zejtun, ZTN3000, Malta.

Marketing Authorization Holder.

UAB "Farmlyga" / JSC "Farmlyga".

Address of Marketing Authorization Holder.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania / Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.