Quentiacs

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) – contained in 25 mg and 100 mg tablets, iron oxide red (E 172) – contained in 25 mg tablets.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

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

Pharmacotherapeutic group. Antipsychotics. Quetiapine.

ATC code N05AH04.

Pharmacological Properties

Pharmacodynamics

Quetiapine is a dibenzothiazepine derivative with antipsychotic activity. Quetiapine and its active metabolite, N-desalkyl quetiapine, 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 of 288 and 557 nM, respectively) and dopamine receptors D1 and D2 (in vitro Ki values of 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 drug's clinical antipsychotic properties, 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 cholinergic muscarinic or benzodiazepine receptors.

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

In addition, similar to quetiapine, N-desalkyl quetiapine 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-desalkyl quetiapine are linear. The pharmacokinetics of quetiapine 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. Maximum plasma concentration is reached approximately 2 hours after oral administration. At steady state, the molar concentration of the active metabolite N-desalkyl quetiapine 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-desalkyl quetiapine, the half-life is approximately 12 hours. On average, less than 5% of the dose of quetiapine and its active metabolite is excreted unchanged in urine.

After 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 one week after dosing. Due to extensive hepatic metabolism, higher plasma concentrations of quetiapine can be expected in patients with hepatic impairment, and dose adjustment may therefore be necessary.

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

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

In vitro studies have shown that quetiapine and some of its metabolites (including N-desalkyl quetiapine) 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 achieved 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 recurrence 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 similar effects and with alcohol.

Caution is advised when administering to patients receiving concomitant medications with anticholinergic (muscarinic) effects (see section "Special precautions for use").

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

In a multiple-dose pharmacokinetic study evaluating quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant use of carbamazepine significantly increased quetiapine clearance. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to an average of 13% of exposure 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 benefits of Quetiapine® therapy outweigh the risks associated with discontinuation of the enzyme inducer. It is important that any changes in the use of the enzyme inducer be made gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see section "Special precautions for use").

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

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

Pharmacokinetics of quetiapine were not altered when administered concomitantly 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 plus Quetiapine® versus placebo plus Quetiapine® in adult patients with acute mania, increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain were observed in the group receiving 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 administering quetiapine concomitantly with medicinal products that affect electrolyte balance or prolong the QT interval.

False positive results in immunoassay screening tests for methadone and tricyclic antidepressants have been reported in patients taking quetiapine. It is recommended that questionable immunoassay screening 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, due to the risk of developing serotonin syndrome, a potentially life-threatening condition (see "Special precautions for use").

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 prescribed 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 studies 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, increased serum prolactin levels, vomiting, rhinitis, and syncope), or may have different consequences in children and adolescents (extrapyramidal symptoms and irritability), and one adverse event not previously observed in adult clinical trials (elevated blood pressure) has been identified. Additionally, changes in thyroid function parameters have been observed in children and adolescents.

The delayed impact of Quetiapex® treatment on growth and sexual maturation has not been studied beyond 26 weeks. The long-term impact on cognitive and behavioral development is 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 is achieved. Since improvement may not occur during the first weeks of treatment or longer, patients should be closely monitored until such improvement occurs. According to general clinical experience, the risk of suicide may increase in the early stages of improvement.

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

Other psychiatric disorders for which Quetiapex® should 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 who demonstrate significant suicidal ideation prior to starting therapy have a 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 warned to monitor for clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical help if 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 younger 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 to 64 years without a history of self-harm when quetiapine was used concomitantly with other antidepressants.

Sedation and dizziness

Treatment with quetiapine is associated with somnolence and similar symptoms such as sedation (see section "Adverse reactions"). In clinical trials, such 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, similar to somnolence, usually occur during the dose titration period. These effects may contribute to an increased frequency of accidental injuries (falls), particularly in elderly patients. Therefore, patients should be advised to be cautious until they become accustomed to the possible effects of the drug.

Cardiovascular disorders

Quetiapex® should be used with caution in patients with cardiovascular and cerebrovascular disorders or other conditions that may lead to arterial hypotension. Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration; therefore, dose reduction or a longer titration period 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 developing sleep apnea. This includes patients who are overweight/obese or male patients.

Seizures

During controlled clinical trials, there was no difference in the incidence 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 incidence 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 these 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 occur after discontinuation of therapy (see section "Adverse reactions").

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome may be associated with treatment with antipsychotics, including quetiapine. Clinical manifestations include hyperthermia, changes in 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 <0.5x10⁹/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 was 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 developing 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 Quetiapex® SR treatment. Such patients should have timely determination of white blood cell count and absolute neutrophil count (ANC), especially in the absence of predisposing factors.

Quetiapine treatment should be discontinued if the neutrophil count in the blood is <1.0 x 10⁹/L. Patients should be monitored for signs of infection and changes in neutrophil levels until levels exceed 1.5 x 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 contributes to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used concomitantly with other drugs having anticholinergic effects at recommended doses or 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 a current diagnosis or history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure, or closed-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 potent 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 using Quetiapex® 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

Weight gain has been reported in patients treated with quetiapine, which should be monitored and managed according to clinical relevance in accordance with recommendations for the use of antipsychotic drugs (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 the use of antipsychotic agents. Patients treated with any antipsychotic drugs, including quetiapine, require monitoring for the emergence of symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes mellitus should be regularly checked for worsening glucose control. Body weight should be continuously monitored.

Lipids

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

Metabolic risk

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

Prolongation of QT interval

In clinical trials and during use according to the medical instructions, quetiapine did not cause sustained increases in absolute QT intervals. In the post-marketing period, QT interval prolongation has been observed with quetiapine 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 disorders 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 treatment with quetiapine, 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 reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or have fatal outcomes, have been reported.

Severe skin adverse reactions are accompanied by one or more 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 occur, 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, an approximately threefold increased risk of cardiovascular adverse events was observed with the use of some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk cannot be excluded with the use of other antipsychotics or in other patient populations. Quetiapex® should be used with caution in patients with risk factors for stroke.

According to a meta-analysis of atypical antipsychotics, elderly patients with psychosis associated with dementia represent a group at increased risk of fatal outcome 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 trials 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 fatal outcome with the use of quetiapine 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 reported with the use of quetiapine. 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"), including fatal cases in patients at higher risk of developing intestinal obstruction, including those receiving concomitant multiple drugs that reduce intestinal peristalsis and/or drugs for which constipation-inducing effects may not have been previously reported. Treatment of patients with intestinal obstruction/volvulus should be conducted under close supervision and with immediate medical intervention.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with the use of 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® and 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, potentially life-threatening (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 documented. 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 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 developmental malformations due to quetiapine treatment. However, based on all available data, a definitive conclusion cannot be drawn. Animal studies have shown reproductive toxicity. Therefore, quetiapine may 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 lead to adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after birth. 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.

Breastfeeding period

Based on very limited data from published reports on the excretion of quetiapine in human breast milk, excretion of quetiapine at therapeutic doses is uncertain. Due to the lack of reliable data, a decision must 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 influence reaction speed when driving vehicles or operating machinery.

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

Method of Administration and Dosage

Different dosing regimens are prescribed for each indication. Ensure that the dosage prescribed to the patient corresponds to their clinical 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 per day) 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 ranges from 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 treating bipolar disorder. Clinical studies indicate that for some patients experiencing poor tolerability, dose reduction down to the minimum of 200 mg should be considered.

Prevention of Disease Recurrence in Bipolar Disorder

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

Elderly Patients

As with other antipsychotics and antidepressants, Quetiapine® should be used cautiously in elderly patients, particularly at the beginning of treatment and during dose titration. 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 is reduced by 30–50% in elderly individuals compared to younger patients.

The safety and efficacy of the medicinal product have not been studied in patients aged 65 years and older with depressive episodes in bipolar disorder.

Renal Impairment

There is no need for dose adjustment in patients with renal impairment.

Hepatic Impairment

Quetiapine is extensively metabolized in the liver. Therefore, Quetiapine® should be administered with caution to patients with hepatic impairment, especially during the initial dose titration period. Treatment in 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 reach an effective dose, depending on clinical response and tolerability in each individual patient.

Children

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

Overdose

Symptoms

Manifestations and symptoms of overdose are due to an exaggeration of known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, arterial 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 be at increased risk of overdose effects (see section "Special Instructions").

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 clear 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 arrhythmia, 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 drug ingestion) and administration of activated charcoal may be considered in cases of severe overdose.

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

Adrenaline (epinephrine) and dopamine should be avoided, as beta-stimulation may worsen hypotension in the setting 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 events during treatment with quetiapine is listed below according to the following classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

From blood and lymphatic system
Very common Common Uncommon Rare	Decreased hemoglobin levels22 Leukopenia1,28, decreased neutrophil count, elevated eosinophil levels27 Thrombocytopenia, anemia, decreased platelet count13, neutropenia1 Agranulocytosis26
From immune system
Uncommon Rare	Hypersensitivity (including skin allergic reactions) Anaphylactic reaction5
From endocrine system
Common Uncommon Very rare	Hyperprolactinemia15, decreased total T424, decreased free T424, decreased total T324, increased TSH24 Decreased free T324, hypothyroidism21 Inappropriate antidiuretic hormone secretion
From metabolism and nutrition
Very common Common Uncommon Rare	Increased serum triglyceride levels10,30, increased total cholesterol (especially LDL cholesterol)11,30, decreased HDL cholesterol17,30, weight gain8,30 Increased appetite, elevated blood glucose levels up to hyperglycemia6,30 Hypotension19, diabetes mellitus1,5, worsening of pre-existing diabetes Metabolic syndrome29
Psychiatric disorders
Common Rare	Unusual dreams and nightmares, suicidal thoughts and suicidal behavior20 Sleepwalking and related phenomena such as sleep talking and sleep-related eating disorder
From nervous system
Very common Common Uncommon	Dizziness4,16, somnolence2,16, headache, extrapyramidal symptoms1,21, dysarthria Seizures1, restless legs syndrome, tardive dyskinesia1,5, syncope4,16 Confusional state
From heart
Common Uncommon Frequency not known	Tachycardia4, palpitations23 QT interval prolongation1,12,18, bradycardia32 Cardiomyopathy, myocarditis
From eye organs
Common	Blurred vision
From vascular system
Common Rare Frequency not known	Orthostatic hypotension4,16 Venous thromboembolism1 Stroke33
From renal and urinary system
Uncommon	Urinary retention
Respiratory, thoracic and mediastinal disorders
Common Uncommon	Dyspnea23 Rhinitis
From gastrointestinal tract
Very common Common Uncommon Rare	Dry mouth Constipation, dyspepsia, vomiting25 Dysphagia7 Pancreatitis1, intestinal obstruction/ileus
From hepatobiliary system
Common Uncommon Rare	Elevated alanine aminotransferase (ALT) in serum3, elevated gamma-GT levels3 Elevated aspartate aminotransferase (AST)3 in serum Jaundice5, hepatitis
From skin and subcutaneous tissue
Very rare Frequency not known	Angioedema5, Stevens-Johnson syndrome5 Toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), skin vasculitis
From musculoskeletal and connective tissue system
Very rare	Rhabdomyolysis
Pregnancy, postpartum and perinatal conditions
Frequency not known	Drug withdrawal syndrome in newborns31, neonatal abstinence syndrome
From reproductive system and breast
Uncommon Rare	Sexual dysfunction Pruritus, galactorrhea, breast swelling, menstrual cycle disturbances
General disorders
Very common Common Rare	Withdrawal symptoms (upon discontinuation)1,9 Mild asthenia, peripheral edema, irritability, pyrexia Malignant neuroleptic syndrome1, hypothermia
Laboratory test changes
Rare	Elevated blood creatine phosphokinase levels14

1. See section "Special precautions".

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

3. Asymptomatic elevations (deviations from normal to >3×ULN at any time) in transaminase (ALT, AST) or gamma-GT (glutamyl transferase) levels were 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 associated with dizziness, tachycardia, and in some patients, syncope, particularly during the 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 ≥126 mg/dL (≥7.0 mmol/L) or postprandial blood glucose ≥200 mg/dL (≥11.1 mmol/L) at least once.

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 compared to baseline. Occurs predominantly during the first weeks of therapy in adults.

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

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

11. Cholesterol level ≥240 mg/dL (≥6.2064 mmol/L) (patients aged ≥18 years) or ≥200 mg/dL (≥5.172 mmol/L) (patients aged <18 years) at least once. 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 at least once.

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 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 ideation and suicidal behaviour 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 haemoglobin level to ≤13 g/dL (8.07 mmol/L) in males, ≤12 g/dL (7.45 mmol/L) in females at least once was observed in 11% of patients treated with quetiapine across all studies, including open-label trials. For these patients, the mean maximum decrease in haemoglobin 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 for total T4, free T4, total T3, and free T3 were <0.8×LLN (pmol/L), and TSH deviation was >5 mIU/L at any time.

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

26. Deviation of 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. 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 initiation of treatment in all studies. Leukocyte deviation was ≤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 during pregnancy or breastfeeding".

32. May occur during or shortly after initiation of therapy and may be associated with hypotension and/or syncope. Incidence 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 skin adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported 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) than in adults, or ADRs not observed in the adult patient group.

Table 2. ADRs in children and adolescents associated with quetiapine treatment that occur more frequently than in adults or are 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 (>1/1000, <1/100), rare (>1/10,000, <1/1000), and 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 Common	Extrapyramidal symptoms3,4 Loss of consciousness
Vascular disorders
Very common	Increased blood pressure2
Respiratory, thoracic and mediastinal disorders
Common	Rhinitis
Gastrointestinal disorders
Very common	Vomiting
General disorders and administration site conditions
Common	Irritability3

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 prolactin levels increased to >100 µg/L.

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

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

4See section “Pharmacodynamics”.

Suspected adverse reaction reporting

Reporting of suspected adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy through 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 and sight 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 business operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.

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