Quetiapax®

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

Composition:

Active substance: quetiapine;

One film-coated tablet contains 25 mg or 100 mg or 200 mg or 300 mg of quetiapine (as quetiapine fumarate);

Excipients: lactose monohydrate, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate (type A), hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide yellow (E 172) – present in 25 mg and 100 mg tablets, iron oxide red (E 172) – present in 25 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• 25 mg film-coated tablets: round, pale red-colored, film-coated tablets with beveled edges;
• 100 mg film-coated tablets: round, yellow-brown colored, film-coated tablets;
• 200 mg film-coated tablets: round, white colored, film-coated tablets;
• 300 mg film-coated tablets: white, capsule-shaped, film-coated tablets.

Pharmacotherapeutic group. Antipsychotics. Quetiapine.

ATC code N05AH04.

Pharmacological properties.

Pharmacodynamics.

Quetiapine is a dibenzothiazepine derivative with antipsychotic activity. Quetiapine and its active metabolite, N-desalkylquetiapine, interact with a wide range of neurotransmitter receptors. The contribution of the N-desalkyl metabolite to the overall pharmacological effect of the drug remains unclear.

Quetiapine exhibits affinity for brain serotonin receptors 5HT2 and 5HT1A (in vitro Ki values are 288 and 557 nM, respectively) and dopamine receptors D1 and D2 (in vitro Ki values are 558 and 531 nM, respectively). This combination of receptor antagonism, with relatively greater selectivity for 5HT2 receptors compared to D2 receptors, is believed to underlie the clinical antipsychotic properties of the drug, as well as its relatively low incidence of extrapyramidal symptoms. Quetiapine also shows high affinity for histamine H1 receptors (in vitro Ki = 10 nM) and alpha 1-adrenergic receptors (in vitro Ki = 13 nM), with lower affinity for alpha 2-adrenergic receptors (in vitro Ki = 782 nM). Quetiapine does not bind to muscarinic cholinergic or benzodiazepine receptors.

N-desalkylquetiapine has a similar affinity profile to quetiapine, showing affinity for brain serotonin 5HT2 receptors and dopamine D1 and D2 receptors.

Additionally, like quetiapine, N-desalkylquetiapine exhibits high affinity for serotonin 5HT1 receptors, histamine H1 receptors, and alpha 1-adrenergic receptors, with lower affinity for alpha 2-adrenergic receptors.

Pharmacokinetics.

Within the clinically relevant dose range, the pharmacokinetics of quetiapine and N-desalkylquetiapine are linear. Quetiapine kinetics do not differ between men and women, or between smokers and non-smokers.

Absorption. Quetiapine is well absorbed from the gastrointestinal tract following oral administration. The bioavailability of quetiapine is practically unchanged when the drug is taken with food, although Cmax and AUC increase by 25% and 15%, respectively. Peak plasma concentrations are reached approximately 2 hours after oral administration. At steady state, the molar concentration of the active metabolite N-desalkylquetiapine is about 35% of that of quetiapine.

Distribution. The volume of distribution of quetiapine is 10 ± 4 L/kg, and plasma protein binding is 83%.

Elimination and metabolism. The elimination half-life of quetiapine is approximately 6–7 hours with repeated dosing at clinically recommended doses. For N-desalkylquetiapine, the half-life is approximately 12 hours. On average, less than 5% of the dose is excreted unchanged in urine as free quetiapine and its active metabolite.

Following administration of radiolabeled quetiapine, approximately 73% of the dose is excreted in urine and 21% in feces within one week.

Quetiapine is extensively metabolized in the liver, and less than 5% of the administered dose is recovered as unchanged compound in urine and feces within one week after administration of radiolabeled quetiapine. Due to extensive hepatic metabolism, higher plasma concentrations of quetiapine can be expected in patients with impaired liver function, and dose adjustment may therefore be necessary.

The main metabolic pathways of quetiapine involve oxidation of the side alkyl chain, hydroxylation of the dibenzothiazepine ring, sulfoxidation, and conjugation (phase 2). The major metabolites of quetiapine in human plasma are oxidation and sulfoxidation products, none of which have pharmacological activity.

The primary cytochrome P450 enzyme responsible for quetiapine metabolism is CYP3A4. Formation of the N-desalkyl metabolite and elimination of quetiapine occur predominantly via this enzyme.

In vitro studies have shown that quetiapine and some of its metabolites (including N-desalkylquetiapine) are weak inhibitors of the cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6, and 3A4. However, this inhibition in vitro occurs only at concentrations 5–50 times higher than those observed in humans receiving quetiapine at doses of 300–800 mg/day.

Clinical characteristics.

Indications.

• Treatment of schizophrenia.
• Treatment of bipolar disorder, specifically:
  • treatment of moderate to severe manic episodes in bipolar disorder;
  • treatment of severe depressive episodes in bipolar disorder;
  • prevention of disease relapse in patients with bipolar disorder, in patients with manic or depressive episodes for whom treatment with quetiapine is effective.

Contraindications.

Hypersensitivity to the active substance or 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, is contraindicated.

Interaction with other medicinal products and other forms of interaction.

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

Caution should be exercised when administering to patients receiving concomitant medications with anticholinergic (muscarinic) effects (see section "Special precautions").

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for quetiapine metabolism. In a study of interaction in healthy volunteers, co-administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) resulted in a 5–8 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 pharmacokinetic study evaluating quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant administration of carbamazepine significantly increased quetiapine clearance. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to approximately 13% of the exposure observed with quetiapine alone, although a greater effect was observed in some patients. Due to this interaction, lower plasma concentrations may occur, potentially affecting the efficacy of Quetiapine® therapy.

Concomitant administration of quetiapine and phenytoin (another microsomal enzyme inducer) resulted in an increase in quetiapine clearance by approximately 450%. Initiation of Quetiapine® therapy in patients receiving a hepatic enzyme inducer should only be considered if the physician determines that the benefit of using Quetiapine® outweighs the risks associated with discontinuation of the hepatic enzyme inducer. It is important that any changes in the administration of the inducer be made gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see section "Special precautions").

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).

Concomitant administration of antipsychotics such as risperidone or haloperidol did not cause significant changes in the pharmacokinetics of quetiapine. Concurrent administration of quetiapine and thioridazine resulted in an increase in quetiapine clearance by approximately 70%.

Pharmacokinetics of quetiapine were not altered when co-administered with cimetidine.

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

In a 6-week randomized study comparing the combination of lithium with Quetiapine® and placebo versus Quetiapine® alone in adult patients with acute mania, increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain were observed in the group receiving added lithium compared to the placebo group (see section "Pharmacological properties").

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 co-administering quetiapine with medicinal products that alter electrolyte balance or prolong the QT interval.

In patients receiving quetiapine, false-positive results in enzyme immunoassays for methadone and tricyclic antidepressants have been reported. It is recommended that suspicious screening immunoassay results be confirmed using an appropriate chromatographic method.

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

Special precautions for use.

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

Long-term efficacy and safety of adjunctive therapy in patients with MDD have not been evaluated, although long-term efficacy and safety of monotherapy with the drug in adult patients have been studied.

Children

Quetiapex® is not recommended for use in children due to lack of data supporting its use in this age group. Clinical trials of quetiapine have shown that, in addition to the known safety profile established in adults, the frequency of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, vomiting, rhinitis, and syncope), or may have different consequences in children and adolescents (extrapyramidal symptoms and irritability). One adverse event not previously observed in adult clinical trials has also been reported (elevated blood pressure). Additionally, changes in thyroid function parameters have been observed in children and adolescents.

The long-term impact of Quetiapex® treatment on growth and sexual maturation has not been studied beyond 26 weeks. The long-term effects on cognitive and behavioral development are unknown.

During placebo-controlled clinical trials of Quetiapex® involving pediatric and adolescent patients, quetiapine treatment was associated with an increased incidence 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 in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission occurs. 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.

In addition, the potential risk of suicide-related events after abrupt discontinuation of quetiapine treatment should be considered.

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

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

Patients with a history of suicide-related events or those exhibiting significant levels of suicidal ideation prior to treatment initiation are at higher risk of developing suicidal thoughts or suicide attempts 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 their caregivers) should be advised to monitor for clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical attention if such symptoms occur.

In short-term placebo-controlled trials involving patients with major depressive episodes in bipolar disorder, 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). In clinical trials involving patients with MDD, the frequency of suicide-related events in young patients (under 25 years of age) was 2.1% (3/144) in the quetiapine group and 1.3% (1/75) in the placebo group. A population-based retrospective study of quetiapine use in patients with major depressive disorder (MDD) showed an increased risk of self-harm and suicide in patients aged 25–64 years without a history of self-harm when quetiapine was used concomitantly with other antidepressants.

Somnolence and dizziness

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

Orthostatic hypotension

Treatment with quetiapine has been associated with orthostatic hypotension and related dizziness (see section "Adverse reactions"), which, like 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 exercise caution until they become accustomed to the possible effects of the drug.

Cardiovascular disorders

Quetiapex® should be used with caution in patients with cardiovascular or cerebrovascular diseases 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 more prolonged titration may be necessary in such cases.

Sleep apnea syndrome

Cases of sleep apnea syndrome have been reported in patients taking quetiapine. Quetiapine should be used with caution in patients who are concurrently taking central nervous system depressants and who have a history of or are at risk for sleep apnea. This includes patients with overweight/obesity or male patients.

Seizures

During controlled clinical trials, there was no difference in the frequency of seizures between patients taking quetiapine and those in the placebo group. As with other antipsychotic drugs, quetiapine should be prescribed with caution in patients with a history of seizures (see section "Adverse reactions").

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.

The use of quetiapine has been associated with the development of akathisia, characterized by subjective distress or unpleasant restlessness and an urge 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 be harmful.

Tardive dyskinesia

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

Malignant neuroleptic syndrome

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

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count <0.5×10⁹/L) has been observed in clinical trials of quetiapine. Most cases of severe neutropenia occurred within two months after starting quetiapine treatment. No clear dose relationship has been established. During the post-marketing period, some cases were fatal. Possible risk factors for neutropenia include pre-existing leukopenia and drug-induced neutropenia in the patient's history. Cases of agranulocytosis have occurred in patients without pre-existing risk factors. The possibility of neutropenia should be considered in patients with infection, especially in the absence of obvious predisposing factors, and in patients with fever of unknown origin, and appropriate clinical measures should be taken.

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

Quetiapine treatment should be discontinued if the neutrophil count in blood is <1.0×10⁹/L. Patients should be monitored for signs of infection and changes in neutrophil levels until levels exceed 1.5×10⁹/L (see section "Pharmacodynamic properties").

Anticholinergic (muscarinic) effects

Norquetiapine, an active metabolite of quetiapine, has moderate to high affinity for several subtypes of muscarinic receptors. This may contribute to adverse reactions reflecting anticholinergic effects when quetiapine is used at recommended doses in combination with other drugs having anticholinergic effects, especially in cases of overdose. Quetiapine should be used with caution in patients receiving medications with anticholinergic (muscarinic) effects.

Quetiapine should be used with caution in patients with a current diagnosis or history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure, or narrow-angle glaucoma (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Adverse reactions").

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 Quetiapex® in patients receiving a hepatic enzyme inducer may be initiated only if the physician considers the benefit of Quetiapex® use to outweigh the risks of discontinuing the 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

Weight gain has been reported in patients treated with quetiapine and should be monitored and managed according to clinical relevance in accordance with recommendations for antipsychotic drug use (see sections "Pharmacodynamics" and "Adverse reactions").

Hyperglycemia

Hyperglycemia or worsening of diabetes mellitus has occasionally been associated with ketoacidosis or coma, rarely observed, including several cases with fatal outcomes (see section "Adverse reactions"). In several cases, patients had increased body weight, which may be a risk factor. Appropriate clinical monitoring should be performed according to current guidelines for antipsychotic drug use. Patients treated with any antipsychotic medicinal product, including quetiapine, require monitoring for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes should be regularly checked for worsening glucose control. Body weight should be continuously monitored.

Lipids

Elevations in triglycerides, low-density lipoprotein (LDL), and total cholesterol, and reductions in high-density lipoprotein (HDL) cholesterol have been observed in clinical trials of quetiapine (see section "Adverse reactions"). Appropriate treatment should be initiated in response to lipid level changes.

Metabolic risk

Due to changes in body weight, blood glucose levels (see hyperglycemia), and lipids observed during clinical trials, metabolic parameters should be assessed at the beginning of treatment, and changes in these parameters should be regularly monitored throughout the course of treatment. Worsening of these parameters should be managed according to clinical relevance (see section "Adverse reactions").

Prolongation of QT interval

During clinical trials and according to instructions for medical use, quetiapine did not cause sustained increases in absolute QT intervals. In the post-marketing period, QT interval prolongation has been observed with quetiapine use at 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. Caution should also be exercised when prescribing quetiapine with other medicinal products known to prolong the QT interval, or when used concomitantly with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, hypertrophy of the heart, hypokalemia, or hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").

Severe skin adverse reactions

It is known that during quetiapine treatment, very rare cases of severe skin adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme, and drug reactions with eosinophilia and systemic symptoms (DRESS), have been reported, which may be life-threatening or fatal.

Severe skin adverse reactions are accompanied by one or more of the following symptoms: extensive skin rash, which may be accompanied by itching or pustules, exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia or neutrophilia. Most of these reactions occurred within 4 weeks after starting quetiapine treatment; some DRESS reactions occurred within 6 weeks after starting quetiapine therapy. If signs and symptoms suggestive of these severe skin reactions appear, quetiapine should be immediately discontinued and alternative treatment options 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, a gradual discontinuation of the drug over a period of at least one to two weeks is recommended (see section "Adverse reactions").

Elderly patients with psychosis associated with dementia

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

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

According to meta-analyses of atypical antipsychotics, elderly patients with psychosis associated with dementia are at increased risk of mortality compared to placebo. Data from two 10-week placebo-controlled trials in one patient group (n=710; mean age 83 years; range 56–99 years) showed a mortality rate of 5.5% in patients treated with quetiapine versus 3.2% in the placebo group. The causes of death during the studies were varied and expected for this patient group.

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

A population-based retrospective study in the treatment of patients with MDD showed an increased risk of mortality with quetiapine use 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 when prescribing quetiapine to elderly patients with PD.

Dysphagia

Dysphagia has been observed with quetiapine use. 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 quetiapine use (see section "Adverse reactions"), including fatal cases in patients at higher risk for intestinal obstruction, including those receiving multiple drugs that reduce intestinal peristalsis and/or drugs for which constipation may not have been previously reported. Patients with intestinal obstruction/volvulus should be treated under close supervision and with immediate medical intervention.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported during treatment with neuroleptic agents. Since patients taking neuroleptics 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 during clinical trials and post-marketing use, but a causal relationship has not been established. In post-marketing reports, many patients had risk factors for pancreatitis such as elevated triglyceride levels (see section "Special precautions for use. Lipids"), gallstones, and alcohol consumption.

Cardiomyopathy and myocarditis

Cases of cardiomyopathy and myocarditis have been reported during clinical trials and the post-marketing period, but 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.

Serotonin syndrome

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

If concomitant treatment with other serotonergic agents is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and during dose increases. Symptoms of serotonin syndrome may include changes in mental 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.

Additional information

Data on the use of quetiapine in combination with divalproex or lithium in moderate to severe manic episodes are limited, but combination therapy was well tolerated (see sections "Adverse reactions" and "Pharmacological properties"). An additive effect was observed by the third week of treatment.

Irrational use and abuse

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

Lactose

Quetiapex® tablets contain lactose. This medicinal product should not be administered to patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

First trimester

A moderate amount of published data on exposed pregnancies (i.e., between 300 and 1000 pregnancy outcomes), including individual case reports and some observational studies, do not indicate an increased risk of congenital malformations due to quetiapine treatment. However, based on all available data, a definitive conclusion cannot be made. Animal studies have shown reproductive toxicity. Therefore, quetiapine should be used during pregnancy only if the benefit justifies the potential risk.

Third trimester

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

Period of breastfeeding

Based on very limited data from published reports on the excretion of quetiapine into human breast milk, excretion of quetiapine at therapeutic doses is uncertain. Due to the lack of reliable data, a decision should be made whether to discontinue breastfeeding or discontinue quetiapine therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

The effect of quetiapine on human fertility has not been evaluated. It is known that in rat studies, effects related to elevated prolactin levels were observed, although they are not directly relevant to humans.

Ability to affect reaction speed when driving or operating machinery.

Since quetiapine primarily affects the central nervous system, patients should not drive or operate machinery until their individual sensitivity to such effects has been determined.

Dosage and Administration

Different dosage regimens are prescribed for each indication. Ensure that the prescribed dose corresponds to the patient's condition.

Treatment of schizophrenia

Quetiapine should be administered twice daily. The daily dose during the first four days is: 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), and 300 mg (day 4). After 4 days of treatment, the dose should be titrated to the usual effective dose of 300–450 mg/day. Depending on clinical response and tolerability, the dose may be adjusted within the range of 150 mg to 750 mg per day.

Treatment of moderate to severe manic episodes in bipolar disorder

Quetiapine should be administered twice daily. The daily dose during the first four days of treatment is: day 1 – 100 mg, day 2 – 200 mg, day 3 – 300 mg, day 4 – 400 mg. Thereafter, the dose may be increased (but not by more than 200 mg daily) up to 800 mg/day by day 6 of treatment.

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

Treatment of depressive episodes in bipolar disorder

Quetiapine 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 with the 600 mg dose compared to the 300 mg dose (see section "Pharmacological properties"). The 600 mg dose may be effective in some patients. Doses above 300 mg should be prescribed only by physicians experienced in the treatment of bipolar disorder. Clinical studies indicate that for some patients with poor tolerability, consideration should be given to reducing the dose to the minimum of 200 mg.

Prevention of disease relapse in bipolar disorder

To prevent subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who responded to Quetiapine SR during acute treatment of bipolar disorder should continue treatment with Quetiapine at the same bedtime dose. The dose of Quetiapine may be adjusted within the dose range of 300 mg to 800 mg/day depending on the individual patient's clinical response and tolerability. It is important that the lowest effective doses are used for maintenance therapy.

Elderly patients

As with other antipsychotics and antidepressants, Quetiapine should be used cautiously in elderly patients, especially at the beginning of treatment and during dose titration. A slower dose titration of Quetiapine 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 individuals compared to younger patients.

The safety and efficacy of the medicinal product in patients aged 65 years and older 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, Quetiapine should be used with caution in patients with hepatic impairment, particularly 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 in increments of 25–50 mg/day to achieve an effective dose, depending on the individual patient's clinical response and tolerability.

Children

The safety and efficacy of quetiapine in the treatment of children have not been established; therefore, the drug should not be used in children and adolescents (under 18 years of age). (See section "Special precautions").

Overdose

Symptoms

Signs and symptoms of overdose were manifestations 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 (see section "Special precautions").

Treatment

There is no specific antidote. In cases of severe intoxication, intensive symptomatic and supportive therapy is required, including maintaining and controlling airway patency, adequate ventilation and oxygenation, and cardiovascular function.

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

Although prevention of absorption has not been studied in quetiapine overdose, gastric lavage (within 1 hour of ingestion) and administration of activated charcoal may be considered in cases of severe overdose.

In cases of quetiapine overdose with persistent hypotension, appropriate measures such as intravenous fluid administration and/or sympathomimetics should be taken.

Epinephrine and dopamine should be avoided, as beta-stimulation may worsen hypotension in the presence of alpha-blockade caused by quetiapine.

Close medical monitoring should continue until the patient has fully recovered.

Adverse Reactions

The most commonly reported adverse reactions during quetiapine administration include: 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 levels, and extrapyramidal symptoms.

As with other antipsychotic agents, quetiapine use has been associated with weight gain, syncope, neuroleptic malignant syndrome, leukopenia, and peripheral edema.

The frequency of adverse reactions during quetiapine treatment is listed below according to the following classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

1. See section "Special precautions".

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

3. Asymptomatic elevations (deviations from normal to >3×ULN at any time) in transaminase levels (ALT, AST) or gamma-GT (glutamyl transferase) have been observed in some patients during quetiapine treatment. These elevations were usually reversible with continued quetiapine therapy.

4. Like other antipsychotic medicinal products that block alpha1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension accompanied by 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 based only on post-marketing data from the use of quetiapine 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) 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 clinical trials, where withdrawal symptoms were assessed: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions decreased substantially 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) on at least one occasion.

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) on at least one occasion. Increases in LDL-cholesterol of ≥30 mg/dL (≥0.769 mmol/L) were very common. The mean value among patients with such LDL-cholesterol increases 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 clinical trial data on adverse reactions, elevations in blood creatine phosphokinase levels were 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 quetiapine studies, mean change and number of patients with deviations to clinically significant levels were similar in quetiapine and placebo groups.

19. Deviation from >132 mmol/L to ≤132 mmol/L at least once.

20. Cases of suicidal thoughts 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 on at least one occasion was observed in 11% of patients treated with quetiapine across all studies, including open-label trials. For these patients, the mean maximum decrease in hemoglobin level at any time was 1.50 g/dL.

23. Frequently observed in the context of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disorders.

24. Based on deviation from normal baseline to potentially clinically significant values at any time after initiation of treatment in all studies. Deviations in total T4, free T4, total T3, and free T3 were defined as <0.8×LLN (pmol/L), and TSH deviation as >5 mU/L at any time.

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

26. Deviation in neutrophil count from baseline ≥1.5×10⁹/L to <0.5×10⁹/L at any time during treatment.

27. Based on deviation from normal baseline to potentially clinically significant values at any time after initiation of treatment in all studies. Eosinophilia deviation was defined as >1×10⁹ cells/L at any time.

28. Based on deviation from normal baseline to potentially clinically significant values at any time after initiation of treatment in all studies. Leukopenia deviation was defined as ≤3×10⁹ cells/L at any time.

29. Based on reports of adverse reactions related to metabolic syndrome from all clinical trials of quetiapine.

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

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

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-type arrhythmia have been reported with the use of neuroleptic medicinal products and are considered class-specific.

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

Paediatric patients

The same ADRs described above in adults should also be considered in children and adolescents. Table 2 summarizes ADRs occurring at a higher frequency in paediatric and adolescent patients (10–17 years) compared to adults, or ADRs not observed in the adult patient group.

Table 2. ADRs in children and adolescents associated with quetiapine treatment occurring more frequently than in adults or not observed in adult patients

The frequency of adverse events is defined according to the following classification: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000), and very rare (<1/10,000).

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

2Based on deviations above clinically significant values (based on National Institute of Health criteria) or an 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.

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

4See section "Pharmacodynamics".

Reporting suspected adverse reactions

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

Shelf life. 5 years.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging.

10 tablets per blister, 3 or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

KRKA-PHARMA d.o.o., Croatia.

Manufacturer's address and location of its operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.

V. Holjevca 20/E, 10450 Jastrebarsko, Croatia.

Date of last review.