Kwetiron® xr asino

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Quetiron®XR Acino (Quetiron XR Acino)

Composition:

Active substance: quetiapine;

One tablet contains 57.56 mg or 172.68 mg or 345.36 mg of quetiapine fumarate, equivalent to 50 mg or 150 mg or 300 mg of quetiapine;

Excipients: methacrylic acid copolymer (type A), anhydrous lactose (SD 250), crystalline maltose (Advantose 100), talc, magnesium stearate (vegetable origin);

Coating composition: methacrylic acid copolymer (type A), triethyl citrate (Citrofol).

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

50 mg: white or almost white, round, biconvex tablets, engraved with "50" on one side;

150 mg: white or almost white, oval, biconvex tablets, engraved with "150" on one side;

300 mg: white or almost white, oval, biconvex tablets, engraved with "300" on one side.

Pharmacotherapeutic group. Drugs acting on the nervous system. Psycholeptics. Antipsychotics. Diazepines, oxazepines, thiazepines and oxepines. Quetiapine.

ATC code: N05AH04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Quetiapine is an atypical antipsychotic medicinal product. Quetiapine and its active plasma metabolite norquetiapine interact with multiple neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for serotonin (5HT2) and dopamine D1 and D2 receptors in the brain. This combination of receptor antagonism, with greater selectivity for 5HT2 than for D2 receptors, is considered to underlie the clinical antipsychotic effects of quetiapine and its low propensity to cause extrapyramidal disorders (EPD) compared to typical antipsychotic medicinal products.

Quetiapine and norquetiapine do not have high affinity for benzodiazepine receptors; however, they have high affinity for histamine receptors and α1-adrenergic receptors, and moderate affinity for α2-adrenergic receptors. Quetiapine has low or no affinity for cholinergic muscarinic receptors, whereas norquetiapine has moderate to high affinity for several muscarinic receptor subtypes, which may explain anticholinergic (muscarinic) effects.

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

Pharmacodynamic Effects

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

Quetiapine blocks the effects of dopamine agonists, as demonstrated by behavioral response assessments or electrophysiological studies, and increases dopamine metabolite concentrations, providing neurochemical evidence of D2 receptor blockade.

In preclinical studies evaluating EPD, quetiapine demonstrated an atypical activity profile and differed from typical antipsychotic medicinal products.

Quetiapine, after prolonged administration, did not lead to supersensitivity of dopaminergic D2 receptors.

Quetiapine, at doses effective for blockade of dopaminergic D2 receptors, caused only mild catalepsy.

Quetiapine demonstrates selectivity for the limbic system by inducing depolarization block of mesolimbic, but not nigrostriatal, dopamine-containing neurons after prolonged administration. Quetiapine shows minimal dystonic liability in haloperidol-sensitive or drug-naive monkeys after single and repeated administration (see section "Adverse Reactions").

Clinical Efficacy

Schizophrenia

The efficacy of prolonged-release quetiapine in the treatment of schizophrenia was demonstrated in one 6-week placebo-controlled study involving patients meeting DSM-IV criteria for schizophrenia, and in one active-controlled study evaluating the switch from immediate-release quetiapine to prolonged-release quetiapine in clinically stable outpatients with schizophrenia.

The primary outcome variable in the placebo-controlled study was change from baseline to endpoint in total Positive and Negative Syndrome Scale (PANSS) score. Results with prolonged-release quetiapine at doses of 400 mg/day, 600 mg/day, and 800 mg/day were associated with statistically significant improvement in psychotic symptoms compared to placebo. The effect at 600 mg and 800 mg doses was greater than at 400 mg.

In a 6-week active-controlled switching study, the primary outcome variable was the proportion of patients demonstrating inadequate response, defined as discontinuation of study treatment due to lack of efficacy or a ≥20% increase in total PANSS score from randomization to any visit. In patients stabilized on immediate-release quetiapine at doses of 400–800 mg, efficacy was maintained when patients were switched to an equivalent daily dose of prolonged-release quetiapine administered once daily.

In a long-term study involving stable patients with schizophrenia treated with prolonged-release quetiapine for 16 weeks, prolonged-release quetiapine was more effective than placebo in preventing relapse. The predicted risk of relapse after 6 months of treatment was 14.3% in the prolonged-release quetiapine treatment group compared to 68.2% in the placebo group. The mean dose was 669 mg. No additional safety data were observed with prolonged-release quetiapine treatment over a period up to 9 months (median 7 months). In particular, reporting of adverse reactions related to EPD and weight gain did not increase with long-term treatment with prolonged-release quetiapine.

Bipolar Disorder

In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy compared to placebo in reducing manic symptoms at 3 and 12 weeks in two monotherapy studies. The efficacy of prolonged-release quetiapine was further demonstrated with significance compared to placebo in an additional 3-week study. Prolonged-release quetiapine was administered in the range of 400–800 mg/day, with a mean dose of approximately 600 mg/day. Data on the use of quetiapine in combination with divalproex or lithium in moderate to severe acute manic episodes are limited at weeks 3 and 6; however, combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.

In a clinical study of patients with depressive episodes in bipolar I or II disorder, treatment with prolonged-release quetiapine at a dose of 300 mg/day demonstrated superior efficacy compared to placebo in reducing total Montgomery-Åsberg Depression Rating Scale (MADRS) score.

In four additional 8-week clinical studies evaluating quetiapine in patients with moderate to severe depressive episodes in bipolar I or II disorder, significant improvement was demonstrated in patients receiving immediate-release quetiapine at doses of 300 mg and 600 mg compared to those receiving placebo, based on corresponding outcome measures: mean improvement in MADRS score and response defined as at least a 50% improvement in total MADRS score from baseline. No difference in effect size was observed between patients receiving 300 mg immediate-release quetiapine and those receiving 600 mg.

In the continuation phase of two of these studies, it was demonstrated that long-term treatment of patients who responded to immediate-release quetiapine 300 or 600 mg was effective compared to placebo treatment for depressive symptoms, but not for manic symptoms.

In two relapse prevention studies evaluating quetiapine in combination with mood stabilizers in patients with manic, depressive, or mixed mood episodes, the combination with quetiapine was superior to monotherapy with mood stabilizers in increasing the time to relapse of any mood episode (manic, mixed, or depressive). Quetiapine was administered twice daily at total daily doses of 400–800 mg/day as combination therapy with lithium or valproate.

In a 6-week randomized study of lithium and prolonged-release quetiapine versus placebo and prolonged-release quetiapine in adult patients with acute mania, the difference in mean improvement from baseline in Young Mania Rating Scale (YMRS) score between the lithium add-on group and the placebo add-on group was 2.8 points, and the difference in the percentage of responders (defined as ≥50% improvement from baseline in YMRS) was 11% (79% in the lithium add-on group versus 68% in the placebo add-on group).

In one long-term study (up to 2 years of treatment) evaluating relapse prevention in patients with manic, depressive, or mixed mood episodes, quetiapine was superior to placebo in increasing the time to relapse of any mood episode (manic, mixed, or depressive) in patients with bipolar I disorder. The number of patients with mood disturbances was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group, and 95 (26.1%) in the lithium treatment group, respectively. In patients who responded to quetiapine, continuation of quetiapine treatment compared to switching to lithium treatment showed that switching to lithium treatment was not associated with an increased time to mood episode relapse.

Major Depressive Episodes in Patients with Major Depressive Disorder (MDD)

In two short-term (6-week) studies, patients who had shown inadequate response to at least one antidepressant were enrolled. Prolonged-release quetiapine at doses of 150 mg/day and 300 mg/day, administered as adjunctive therapy to ongoing antidepressant treatment (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine), demonstrated superiority over antidepressant monotherapy in reducing depressive symptoms, measured by improvement in total MADRS score (mean LS change compared to placebo was 2–3.3 points).

Long-term efficacy and safety of use as adjunctive therapy in patients with MDD have not been evaluated; however, long-term efficacy and safety of use as monotherapy in adults have been evaluated (see below).

The following studies were conducted using prolonged-release quetiapine as monotherapy, but prolonged-release quetiapine is indicated only for use as adjunctive therapy.

In three of four short-term (up to 8 weeks) monotherapy studies in patients with MDD, prolonged-release quetiapine at doses of 50 mg/day, 150 mg/day, and 300 mg/day demonstrated superior efficacy compared to placebo in reducing depressive symptoms, measured by improvement in total Montgomery-Åsberg Depression Rating Scale (MADRS) score (mean LS change compared to placebo was 2–4 points).

In a relapse prevention study using monotherapy in patients with depressive episodes stabilized during open-label treatment with prolonged-release quetiapine for at least 12 weeks, patients were randomized to either once-daily prolonged-release quetiapine or placebo for 52 weeks. The mean dose of prolonged-release quetiapine during the randomized phase was 177 mg/day. The relapse rate was 14.2% in patients receiving prolonged-release quetiapine and 34.4% in patients receiving placebo.

In a short-term (9-week) study in elderly patients (66–89 years) without dementia with major depressive disorder, prolonged-release quetiapine, individually dosed in the range of 50–300 mg/day, demonstrated superior efficacy compared to placebo in reducing depressive symptoms, measured by improvement in total MADRS score (mean LS change compared to placebo was -7.54). In this study, patients randomized to prolonged-release quetiapine received 50 mg/day on days 1–3, dose could be increased to 100 mg/day on day 4, to 150 mg/day on day 8, and to 300 mg/day depending on clinical response and tolerability. The mean dose of prolonged-release quetiapine was 160 mg/day. Except for the frequency of extrapyramidal symptoms (see sections "Adverse Reactions" and "Clinical Safety" below), tolerability of once-daily prolonged-release quetiapine in elderly patients was comparable to that observed in adult patients (18–65 years). The proportion of randomized patients aged 75 years or older was 19%.

Clinical Safety

In short-term placebo-controlled clinical studies in schizophrenia and bipolar mania, the aggregated frequency of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine vs. 8.0% for placebo; bipolar mania: 11.2% for quetiapine vs. 11.4% for placebo). A higher frequency of extrapyramidal symptoms was observed in patients receiving quetiapine compared to those receiving placebo in short-term placebo-controlled clinical studies in MDD and bipolar depression. In short-term placebo-controlled studies of bipolar depression, the aggregated frequency of extrapyramidal symptoms was 8.9% for quetiapine versus 3.8% for placebo. In short-term placebo-controlled monotherapy studies in major depressive disorder, the aggregated frequency of extrapyramidal symptoms was 5.4% for prolonged-release quetiapine versus 3.2% for placebo. In a short-term placebo-controlled monotherapy study in elderly patients with major depressive disorder, the aggregated frequency of extrapyramidal symptoms was 9.0% for prolonged-release quetiapine versus 2.3% for placebo. In both bipolar depression and MDD, the frequency of individual adverse reactions (e.g., akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, psychomotor hyperactivity, and muscle rigidity) did not exceed 4% in any treatment group.

In short-term (3 to 8 weeks) fixed-dose placebo-controlled studies (50–800 mg/day), the mean weight gain in patients receiving quetiapine ranged from 0.8 kg for the 50 mg/day dose to 1.4 kg for the 600 mg/day dose (with lower gain at the 800 mg/day dose) compared to 0.2 kg in patients receiving placebo. The percentage of patients receiving quetiapine who gained ≥7% body weight ranged from 5.3% for the 50 mg/day dose to 15.5% for the 400 mg/day dose (with lower increases at 600 mg and 800 mg daily doses) compared to 3.7% in patients receiving placebo.

A 6-week randomized study comparing lithium and prolonged-release quetiapine versus placebo and prolonged-release quetiapine in adult patients with acute mania showed that the combination of prolonged-release quetiapine with lithium led to a higher number of adverse reactions (63% vs. 48% in prolonged-release quetiapine combined with placebo). Safety results showed a higher frequency of extrapyramidal symptoms reported in 16.8% of patients in the lithium add-on group versus 6.6% in the placebo add-on group, mostly tremor, reported in 15.6% of patients in the lithium add-on group versus 4.9% in the placebo add-on group. The frequency of somnolence was higher in the group receiving prolonged-release quetiapine with lithium add-on (12.7%) compared to the group receiving prolonged-release quetiapine with placebo add-on (5.5%). Additionally, a higher percentage of patients in the lithium add-on group (8.0%) experienced weight gain (≥7%) at end of treatment compared to patients in the placebo add-on group (4.7%).

Long-term relapse prevention studies had an open-label period (4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were randomized to receive quetiapine or placebo. In patients randomized to receive quetiapine, the mean weight gain during the open-label period was 2.56 kg, and by week 48 of the randomized period, the mean weight gain was 3.22 kg compared to open-label baseline. In patients randomized to receive placebo, the mean weight gain during the open-label period was 2.39 kg, and by week 48 of the randomized period, the mean weight gain was 0.89 kg compared to open-label baseline.

In placebo-controlled studies in elderly patients with psychosis associated with dementia, the frequency of cerebrovascular adverse reactions per 100 patient-years was not higher in patients receiving quetiapine than in those receiving placebo.

In all short-term placebo-controlled monotherapy studies in patients with baseline neutrophil levels ≥1.5 × 10⁹/L, the frequency of at least one shift to neutrophil count <1.5 × 10⁹/L was 1.9% in patients receiving quetiapine versus 1.5% in patients receiving placebo. The frequency of shifts to >0.5–<1.0 × 10⁹/L was the same (0.2%) in patients receiving quetiapine and those receiving placebo. In all clinical studies (placebo-controlled, open-label, active comparator), in patients with baseline neutrophil levels ≥1.5 × 10⁹/L, the frequency of at least one decrease in neutrophil count to <1.5 × 10⁹/L was 2.9%, and to <0.5 × 10⁹/L was 0.21% in patients receiving quetiapine.

Treatment with quetiapine was associated with dose-dependent reduction in thyroid hormone levels. The frequency of thyroid-stimulating hormone (TSH) level disturbances was 3.2% for quetiapine versus 2.7% for placebo. Cases of reciprocal, potentially clinically significant fluctuations in both T3 or T4 and TSH in these studies were rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. Reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further decline during long-term treatment. In approximately two-thirds of all cases, discontinuation of quetiapine treatment was associated with reversal of the effect on total and free T4 levels, regardless of treatment duration.

Cataract/Lens Opacities

In a clinical study evaluating the cataractogenic potential of quetiapine (200–800 mg/day) compared to risperidone (2–8 mg/day) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with increased lens opacity grade was not higher with quetiapine (4%) than with risperidone (10%) in patients with at least 21 months of exposure.

Pediatric Population

Clinical Efficacy

The efficacy and safety of quetiapine were evaluated in a 3-week placebo-controlled study for the treatment of mania (n = 284, patients from the US aged 10–17 years). Approximately 45% of patients had an additional diagnosis of ADHD. Additionally, a 6-week placebo-controlled study was conducted for the treatment of schizophrenia (n = 222 patients aged 13–17 years). In both studies, patients known to be non-responsive to quetiapine were excluded. Quetiapine treatment was initiated at a dose of 50 mg/day, increased to 100 mg/day on day 2. Subsequently, the dose was titrated to the target dose (mania: 400–600 mg/day; schizophrenia: 400–800 mg/day) in 100 mg/day increments, administered twice or three times daily.

In the mania study, the difference in mean LS change from baseline in total Young Mania Rating Scale (YMRS) score (active minus placebo) was -5.21 for quetiapine 400 mg/day and -6.56 for quetiapine 600 mg/day. The response rate (YMRS improvement ≥50%) was 64% for quetiapine 400 mg/day, 58% for 600 mg/day, and 37% in the placebo group.

In the schizophrenia study, the difference in mean LS change from baseline in total PANSS score (active minus placebo) was -8.16 for quetiapine 400 mg/day and -9.29 for quetiapine 800 mg/day. Neither low doses (400 mg/day) nor high doses (800 mg/day) of quetiapine exceeded the placebo group in the percentage of patients achieving response, defined as a ≥30% reduction from baseline in total PANSS score. In both mania and schizophrenia, higher doses resulted in numerically lower response rates.

In a third short-term placebo-controlled monotherapy study with prolonged-release quetiapine in children and adolescent patients (10–17 years) with bipolar depression, efficacy was not demonstrated.

There are no data on maintenance of effect or relapse prevention in this age group.

Clinical Safety

In the short-term pediatric studies with quetiapine described above, the frequency of EPD in the active group versus placebo was 12.9% versus 5.3% in the schizophrenia study, 3.6% versus 1.1% in the bipolar mania study, and 1.1% versus 0% in the bipolar depression study. The rate of weight gain ≥7% from baseline body weight in the active group versus placebo was 17% versus 2.5% in the schizophrenia and bipolar mania studies and 13.7% versus 6.8% in the bipolar depression study. The frequency of suicide-related events in the active group versus placebo was 1.4% versus 1.3% in the schizophrenia study, 1.0% versus 0% in the bipolar mania study, and 1.1% versus 0% in the bipolar depression study. During the extended post-treatment observation phase in the bipolar depression study, two additional suicide-related events were observed in two patients. One of these patients was receiving quetiapine at the time of the event.

Long-term Safety

A 26-week open-label study (n = 380 patients) with individualized quetiapine dosing of 400–800 mg/day provided additional safety data. Increased blood pressure in children and adolescents, as well as increased appetite, extrapyramidal symptoms, and increased serum prolactin levels, were reported more frequently in children and adolescents than in adult patients (see sections "Special Populations" and "Adverse Reactions"). Regarding weight gain, after adjustment for normal growth in the long term, an increase of at least 0.5 standard deviations from baseline body mass index (BMI) was used as a measure of clinically significant change; 18.3% of patients treated with quetiapine for at least 26 weeks met this criterion.

Pharmacokinetics

Absorption

Quetiapine is well absorbed after oral administration. Peak plasma concentrations (Tmax) of quetiapine and norquetiapine are reached approximately 6 hours after quetiapine administration. Peak molar concentrations at steady state of the active metabolite norquetiapine are 35% of those of quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear and dose-proportional up to 800 mg inclusive when administered once daily. When comparing equivalent total daily doses of quetiapine administered once daily with immediate-release quetiapine (immediate-release quetiapine fumarate) administered twice daily, the area under the concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (Cmax) is 13% lower at steady state. When comparing prolonged-release quetiapine with immediate-release quetiapine, the AUC of the metabolite norquetiapine is 18% lower for prolonged-release quetiapine.

In a study evaluating the effect of food on quetiapine bioavailability, it was found that high-fat meals caused a statistically significant increase in Cmax and AUC of quetiapine by approximately 50% and 20%, respectively. It cannot be excluded that the effect of a medicinal product containing quetiapine may be higher under the influence of high-fat meals. Light meals do not have a significant effect on Cmax and AUC of quetiapine. Quetiapine is recommended to be taken once daily on an empty stomach.

Distribution

Approximately 83% of quetiapine is bound to plasma proteins.

Metabolism

Quetiapine is extensively metabolized in the liver; use of radiolabeled quetiapine revealed that less than 5% of quetiapine is excreted unchanged in urine or feces.

In vitro studies have shown that CYP3A4 is the primary cytochrome P450 enzyme responsible for quetiapine metabolism. Formation and elimination of norquetiapine occur predominantly via the CYP3A4 isoenzyme. Approximately 73% of radiolabeled substance is excreted in urine and 21% in feces.

Quetiapine and some of its metabolites (including norquetiapine) exhibit weak inhibitory effects in vitro on CYP1A2, 2C9, 2C19, 2D6, and 3A4 isoenzymes of the cytochrome P450 system.

Inhibition of CYP isoenzymes in vitro occurred only at concentrations 5–50 times higher than those achieved with human doses in the range of 300–800 mg daily.

Based on these in vitro results, it is unlikely that concomitant administration of quetiapine with other active substances will lead to clinically significant inhibition of metabolism of other active substances mediated by cytochrome P450. Animal studies have shown that quetiapine may induce cytochrome P450 enzymes. However, in a specific drug interaction study in patients with psychosis, no increase in cytochrome P450 activity was observed after quetiapine administration.

Elimination

The elimination half-life of quetiapine and norquetiapine is approximately 7 and 12 hours, respectively. Approximately 73% of radiolabeled material is excreted in urine and 21% in feces. Less than 5% of the total radioactivity of free quetiapine and active metabolite norquetiapine is excreted in urine as the mean molar fraction of the dose in humans.

Special Populations

Gender

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

Elderly

The mean clearance of quetiapine in elderly individuals is approximately 30–50% lower than in adults aged 18–65 years.

Renal Impairment

The mean plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), but individual clearance values are within the range typical for healthy individuals.

Hepatic Impairment

The mean plasma clearance of quetiapine is reduced by approximately 25% in patients with known hepatic impairment (stable alcoholic cirrhosis). Since quetiapine is extensively metabolized in the liver, increased plasma levels are expected in patients with hepatic impairment. Dose adjustment may be required for such patients (see section "Dosage and Administration").

Children

Pharmacokinetic data are available from children receiving 400 mg quetiapine twice daily. At therapeutic doses, the levels of the parent compound quetiapine in children and adolescents (10–17 years) are generally similar to those in adults, although Cmax in children is higher than in adults. AUC and Cmax for norquetiapine are higher, approximately 62% and 49% in children (10–12 years) and 28% and 14% in adolescents (13–17 years), respectively, compared to adults.

There is no information on the use of the medicinal product Quetiron® XR Acino in children and adolescents.

Clinical Characteristics

Indications

The medicinal product Quetiron® XR Asino is indicated for the treatment of:

• Schizophrenia, including prevention of relapse in patients with stable schizophrenia who have been maintained on Quetiron® XR Asino therapy.
• Bipolar disorder, specifically:
  • for treatment of moderate to severe manic episodes in bipolar disorder;
  • for treatment of severe depressive episodes in bipolar disorder;
  • for prevention of recurrence in patients with bipolar disorder who have responded to Quetiron® XR Asino during manic or depressive episodes.
• As adjunctive therapy in severe depressive episodes in patients with major depressive disorder (MDD) who have had a suboptimal response to antidepressant monotherapy. Prior to initiating therapy, physicians should carefully consider the safety profile of Quetiron® XR Asino.

Contraindications

Hypersensitivity to the active substance or to any component of Quetiron® XR Asino.

Concomitant use with cytochrome P450 3A4 (CYP3A4) inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone, is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction

Since quetiapine primarily affects the central nervous system, the medicinal product should be used with caution in combination with other centrally acting medicinal products and alcohol.

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

Caution should be exercised when treating patients who are taking other medicinal products with anticholinergic (muscarinic) effects (see section "Special precautions for use").

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for CYP-mediated metabolism of quetiapine. In interaction studies in healthy volunteers, concomitant administration of quetiapine (25 mg dose) with ketoconazole, a CYP3A4 inhibitor, resulted in a 5- to 8-fold increase in quetiapine AUC. Therefore, concomitant use of quetiapine with CYP3A4 inhibitors is contraindicated. Grapefruit juice should also not be consumed during quetiapine treatment.

In a multiple-dose pharmacokinetic study evaluating quetiapine administered before and during treatment with carbamazepine (a known hepatic enzyme inducer), concomitant use of carbamazepine was shown to significantly increase quetiapine clearance. This, in turn, reduced systemic exposure to quetiapine (measured as AUC) to approximately 13% of exposure observed with quetiapine alone, although a more pronounced effect was observed in some patients. Due to this interaction, lower plasma concentrations of quetiapine may occur, potentially affecting the efficacy of quetiapine therapy.

Concomitant administration of quetiapine and phenytoin (another hepatic enzyme inducer) resulted in a significant increase in quetiapine clearance by approximately 450%. Initiation of quetiapine therapy in patients receiving a hepatic enzyme inducer should only be considered when, in the physician’s opinion, the benefit of quetiapine outweighs the risk associated with discontinuation of the hepatic enzyme inducer. Importantly, any replacement of the inducer should be done gradually. If necessary, it should be replaced with a non-inducer, such as sodium valproate (see section "Special precautions for use").

The pharmacokinetics of quetiapine are not significantly altered when administered concomitantly with antidepressants such as imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).

Concomitant use of other antipsychotics such as risperidone or haloperidol did not result in significant changes in quetiapine pharmacokinetics. However, concomitant administration of quetiapine and thioridazine resulted in an approximately 70% increase in quetiapine clearance.

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

Lithium pharmacokinetics were not altered when co-administered with quetiapine.

In a 6-week randomized study comparing lithium plus quetiapine versus placebo plus quetiapine in adult patients with acute mania, the addition of lithium was associated with increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain compared to placebo addition (see section "Pharmacodynamic properties").

No clinically significant changes in the pharmacokinetics of sodium valproate or quetiapine were observed when administered concomitantly. A retrospective study in children and adolescents receiving valproate, quetiapine, or both medicinal products revealed a higher incidence of leukopenia and neutropenia in the combination therapy group compared to monotherapy groups.

Formal interaction studies with the most commonly used cardiovascular medicinal products have not been conducted.

Caution should be exercised when administering quetiapine concomitantly with medicinal products that disrupt 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 questionable screening immunoassay results be confirmed using an appropriate chromatographic method.

Special precautions for use

Since quetiapine is indicated for the treatment of schizophrenia, bipolar disorder, and adjunctive treatment of depressive episodes in patients with MDD, the safety profile of the medicinal product Kuetiron® XR Asino should be carefully considered with regard to the specific diagnosis established for the individual patient and the dose being administered.

Long-term efficacy and safety of adjunctive therapy in patients with MDD have not been evaluated; however, long-term efficacy and safety of quetiapine monotherapy in adult patients have been studied (see section "Pharmacological properties").

Children

Quetiapine is not recommended for use in children under 18 years of age 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 for adults (see section "Undesirable effects"), the frequency of certain adverse reactions is higher in children and adolescents than in adults (increased appetite, elevated serum prolactin levels, vomiting, rhinitis, and loss of consciousness), or may have different consequences in children and adolescents (extrapyramidal symptoms (EPS) 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.

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

In placebo-controlled clinical trials involving pediatric and adolescent patients, quetiapine treatment was associated with an increased frequency of EPS compared to placebo in patients treated for schizophrenia and bipolar mania (see section "Undesirable effects").

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal events and behaviors). This risk persists until significant/definite remission occurs. Since improvement may not occur during the first few weeks or longer of treatment, 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 recovery.

In addition, physicians should consider the potential risk of suicidal events and behaviors following abrupt discontinuation of quetiapine treatment due to known risk factors associated with the condition being treated.

Other psychiatric disorders for which quetiapine is prescribed may also be associated with an increased risk of suicidal events and behaviors. These conditions may coexist with severe depressive episodes. Therefore, the same precautions should be taken when treating patients with other psychiatric disorders as when treating patients with severe depressive episodes.

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

Close monitoring of patients, particularly those at high risk, should complement pharmacological treatment, especially during the early stages of treatment and following dose adjustments. Patients (and caregivers) should be advised to monitor for any clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical attention if these symptoms occur.

In short-term placebo-controlled clinical trials involving patients with major depressive episodes in bipolar disorder, an increased risk of suicidal events and behaviors was observed in young patients (under 25 years of age) treated with quetiapine compared to those receiving placebo (3.0% vs. 0%, respectively). In clinical trials among patients with major depressive disorder (MDD), the frequency of suicidal events and behaviors 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 retrospective population analysis of quetiapine use in MDD patients revealed an increased risk of self-harm and suicide in patients aged 24 to 64 years without a history of self-harm during treatment with quetiapine combined with other antidepressants.

Metabolic risk

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

Extrapyramidal symptoms

In placebo-controlled clinical trials involving adult patients, quetiapine use was associated with an increased frequency of EPS compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder (see section "Undesirable effects").

Quetiapine use has been associated with the development of akathisia, characterized by subjective distress or stress-related restlessness and an urge to move, often accompanied by an inability to sit or stand still. These events are most likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may be harmful.

Tardive dyskinesia

If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing quetiapine. Tardive dyskinesia symptoms may worsen or even emerge after discontinuation of therapy (see section "Undesirable effects").

Drowsiness and dizziness

Treatment with quetiapine is associated with drowsiness and other similar symptoms, such as sedation (see sections "Pharmacological properties" and "Undesirable effects"). In clinical trials of patients with bipolar depression and MDD, such symptoms typically occurred within the first 3 days of treatment and were predominantly mild to moderate in intensity. Patients experiencing severe drowsiness may require more frequent monitoring for at least 2 weeks after the onset of drowsiness or until symptoms resolve. After this period, discontinuation of treatment may need to be considered.

Orthostatic hypotension

Treatment with quetiapine has been associated with orthostatic hypotension and related dizziness (see section "Undesirable effects"), which, like drowsiness, usually occur during the initial dose titration period. This may increase the frequency of accidental injuries (falls), especially in elderly patients. Therefore, patients should be advised to be cautious until they become accustomed to the possible effects of the drug.

Quetiapine should be used with caution in patients with known cardiovascular, cerebrovascular diseases, or other conditions that may lead to arterial hypotension. Dose reduction or longer dose titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.

Sleep apnea syndrome

Cases of sleep apnea syndrome have been reported in patients taking quetiapine. Therefore, the medicinal product Kuetiron® XR Asino should be used with caution in patients who are concurrently taking central nervous system depressants, as well as in patients with a history of sleep apnea or those in high-risk groups. This includes patients with excess body weight/obesity, or male patients.

Seizures

Controlled clinical trials did not reveal differences in seizure frequency between patients taking quetiapine or placebo. There are no data on seizure frequency in patients with a history of epilepsy. As with other antipsychotic drugs, quetiapine should be prescribed with caution in patients with a history of seizures (see section "Undesirable effects").

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome (MNS) has been associated with treatment with antipsychotic drugs, including quetiapine (see section "Undesirable effects"). Clinically, MNS presents with hyperthermia, altered mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, quetiapine should be discontinued and appropriate medical treatment initiated.

Serotonin syndrome

Concomitant use of Kuetiron® XR Asino with other serotonergic medicinal products, such as MAO inhibitors, SSRIs, SNRIs, or tricyclic antidepressants, may lead to serotonin syndrome—a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic medicinal products is clinically justified, close monitoring of the patient is recommended, particularly at the beginning of treatment and during dose escalation.

Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

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

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count < 0.5 × 10⁹/L) 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. Several potential risk factors for neutropenia exist: prior low leukocyte count and drug-induced neutropenia in medical history. However, some cases occurred in patients without pre-existing risk factors. Quetiapine should be discontinued in patients with neutrophil counts < 1.0 × 10⁹/L. Monitoring for signs and symptoms of infection and neutrophil counts should continue until levels exceed 1.5 × 10⁹/L (see section "Pharmacological properties").

Neutropenia should be considered in patients with infection and fever, especially in the absence of obvious predisposing factors, and managed according to clinical appropriateness.

Patients should be advised to immediately report signs/symptoms associated with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during quetiapine therapy. These patients should promptly undergo leukocyte count and absolute neutrophil count (ANC) determination, especially in the absence of predisposing factors.

Anticholinergic (muscarinic) effects

Norquetiapine, the active metabolite of quetiapine, has moderate to high affinity for several muscarinic receptor subtypes. This leads to anticholinergic-type adverse reactions when quetiapine is used at recommended doses, when co-administered with other anticholinergic drugs, or in cases of overdose. Quetiapine should be used with caution in patients receiving drugs with anticholinergic (muscarinic) effects. Quetiapine should also be used with caution in patients with existing diagnoses or history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure, or angle-closure glaucoma (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Undesirable effects").

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 affect the efficacy of quetiapine therapy. Treatment with quetiapine in patients receiving a hepatic enzyme inducer should only be initiated if the physician considers the benefit of quetiapine use to outweigh the risk of discontinuing the enzyme inducer. Any changes in the use of the inducer should occur gradually; if necessary, it should be replaced with a non-inducer (e.g., sodium valproate).

Body weight

Weight gain has been reported in patients treated with quetiapine. Therefore, body weight should be monitored and managed according to clinical appropriateness in accordance with recommendations for antipsychotic drugs (see sections "Pharmacological properties" and "Undesirable effects").

Hyperglycemia

Hyperglycemia and/or development or exacerbation of diabetes mellitus have occasionally been associated with ketoacidosis or coma, rarely reported, including several fatal cases (see section "Undesirable effects"). Several cases have been reported with prior weight gain, which may be a predisposing factor for hyperglycemia and/or development or exacerbation of diabetes mellitus. Appropriate clinical monitoring should be conducted according to existing recommendations for antipsychotic drugs. Patients treated with any antipsychotic drugs, including quetiapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes 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, as well as decreases in high-density lipoprotein (HDL) cholesterol, have been observed in clinical trials of quetiapine (see section "Undesirable effects"). Lipid level changes should be managed according to clinical appropriateness.

QT interval prolongation

Based on clinical trials where quetiapine was administered according to the Instructions for Medical Use, the medicinal product did not cause sustained absolute QT interval prolongation. During the post-marketing period, QT interval prolongation has been reported with quetiapine at therapeutic doses (see section "Undesirable effects") 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 a family history of prolonged QT interval. Caution is also advised when prescribing quetiapine with other drugs that prolong the QT interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").

Cardiomyopathy and myocarditis

Cases of cardiomyopathy and myocarditis have been reported in clinical trials and post-marketing surveillance (see section "Undesirable effects"). In patients suspected of having cardiomyopathy or myocarditis, discontinuation of quetiapine treatment should be considered.

Severe cutaneous adverse reactions

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

SCAR typically present with one or more of the following symptoms: extensive skin rash, which may be accompanied by itching or pustule formation, exfoliative dermatitis, fever, lymphadenopathy, and eosinophilia or neutrophilia. Most of these reactions occurred within four weeks after starting quetiapine therapy, and some cases of DRESS syndrome were observed within six weeks after initiation of 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 medicinal product

Acute withdrawal symptoms (insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability) have been described following abrupt discontinuation of quetiapine. Therefore, a gradual discontinuation of the medicinal product over at least one to two weeks is recommended (see section "Undesirable effects").

Elderly patients with psychosis associated with dementia

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

In randomized placebo-controlled trials in dementia patients, use of some atypical antipsychotics was associated with approximately a threefold increased risk of cerebrovascular adverse reactions. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or other patient populations. Quetiapine should be used with caution in patients with stroke risk factors.

Meta-analysis data on atypical antipsychotics indicate that elderly patients with psychosis associated with dementia are at increased risk of mortality compared to the placebo group. However, data from two 10-week placebo-controlled studies evaluating quetiapine in the same patient category (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. In these studies, patients died from various causes expected in this population.

Elderly patients with Parkinson's disease/parkinsonism

A retrospective population analysis of quetiapine use in MDD patients demonstrated an increased risk of mortality during quetiapine treatment in patients over 65 years of age. These data were not confirmed when patients with Parkinson's disease were excluded from the analysis. Caution should be exercised when prescribing quetiapine to elderly patients with Parkinson's disease.

Dysphagia

Cases of dysphagia have been reported with quetiapine use (see section "Undesirable effects"). Quetiapine should be used with caution in patients at risk of aspiration pneumonia.

Constipation and intestinal obstruction

Constipation is a risk factor for intestinal obstruction. Cases of constipation and obstruction have been reported with quetiapine use (see section "Undesirable effects"), including fatal cases in patients at higher risk of intestinal obstruction, including those receiving multiple drugs that reduce intestinal motility and/or drugs not previously associated with constipation symptoms. 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 antipsychotic drugs. Since patients treated with antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during quetiapine treatment, and preventive measures taken.

Pancreatitis

Cases of pancreatitis have been reported during clinical trials and post-marketing use of quetiapine. In post-marketing reports, although not all cases had risk factors, many patients had known risk factors for pancreatitis: elevated triglyceride levels, gallstones, and alcohol consumption.

Additional information

Data on quetiapine use in combination with divalproex or lithium in moderate to severe acute manic episodes are limited, but combination therapy was well tolerated (see sections "Pharmacological properties" and "Undesirable effects"). These data showed an additive effect by the third week of treatment.

Lactose

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

Irrational use and abuse

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

Use during pregnancy or breastfeeding

Pregnancy

First trimester

A moderate amount of published data on pregnancy exposure (i.e., between 300 and 1000 pregnancy outcomes), including individual case reports and some observational studies, does 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 should be used during pregnancy only if the expected benefit justifies the potential risk.

Third trimester

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 birth. Reports include agitation, arterial hypertension, arterial hypotension, tremor, drowsiness, 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 quetiapine excretion in 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 mother.

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 these are not directly relevant to humans.

Ability to affect reaction speed when driving or operating machinery

Due to the primary effect of quetiapine on the central nervous system, it may adversely affect activities requiring concentration. Therefore, patients should be advised to avoid driving and operating machinery until their individual sensitivity to this effect is determined.

Method of Administration and Dosage

Different dosing regimens exist for each indication. Ensure that the patient receives a dose appropriate for their condition.

The medicinal product Kvetiron® XR Asino should be administered once daily on an empty stomach. Tablets should be swallowed whole, without breaking, chewing, or crushing.

Treatment of schizophrenia and moderate to severe manic episodes in bipolar disorder

Kvetiron® XR Asino should be administered at least 1 hour before food intake. The initial daily dose is 300 mg on the first day and 600 mg on the second day. The recommended daily dose is 600 mg; however, if clinically justified, the dose may be increased up to 800 mg/day. The dose should be adjusted within the effective dose range of 400–800 mg/day, depending on clinical response and tolerability. No dose adjustment is required for maintenance therapy in schizophrenia.

Treatment of depressive episodes in bipolar disorder

Kvetiron® XR Asino should be administered at bedtime. The total daily dose during the first four days of treatment is 50 mg (on Day 1), 100 mg (on Day 2), 200 mg (on Day 3), and 300 mg (on Day 4). The recommended daily dose is 300 mg. Clinical trials did not demonstrate 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 a physician experienced in treating bipolar disorder. Clinical studies suggest that for individual patients experiencing tolerability issues, the dose should be reduced to the minimum effective dose of 200 mg.

Prevention of relapse in bipolar disorder

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

Adjunctive treatment of major depressive episodes in MDD

Kvetiron® XR Asino should be taken at bedtime. The initial daily dose is 50 mg on Days 1 and 2, and 150 mg on Days 3 and 4. In short-term adjunctive trials (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine), antidepressant effects were observed at doses of 150 mg/day and 300 mg/day. A dose of 50 mg/day was effective in a short-term monotherapy study. The risk of adverse reactions increases with higher doses. Therefore, physicians should ensure that the lowest effective dose is used, starting at 50 mg/day. Dose increases from 150 mg to 300 mg/day should be based on individual patient assessment.

Switching from Kvetiron immediate-release tablets

Patients currently receiving Kvetiron (immediate-release tablets) may be switched to Kvetiron® XR Asino at an equivalent total daily dose administered once daily for easier dosing. Individual dose adjustments may be necessary.

Elderly patients

As with other antipsychotics and antidepressants, quetiapine should be used with caution in elderly patients, particularly during initiation of treatment and dose titration. Slower titration of quetiapine may be required, and the daily therapeutic dose may be lower than that used in younger patients. Mean plasma clearance of quetiapine is reduced by 30–50% in elderly subjects compared to younger patients. Treatment in elderly patients should be initiated at a dose of 50 mg/day. The dose may be gradually increased by 50 mg/day to achieve an effective dose, depending on individual clinical response and tolerability.

In elderly patients with major depressive episodes in MDD, treatment should be initiated at 50 mg/day on Days 1–3, increased to 100 mg/day on Day 4, and to 150 mg/day on Day 8. The lowest effective dose should be used, starting at 50 mg/day. If, based on individual patient assessment, dose increase to 300 mg/day is required, it should not be initiated earlier than 22 days after starting treatment.

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

No dose adjustment is necessary for patients with renal impairment.

Hepatic impairment

Quetiapine is extensively metabolized in the liver. Therefore, quetiapine should be used with caution in patients with known hepatic impairment, especially during the initial dose titration period. Treatment in patients with hepatic impairment should be initiated at a dose of 50 mg/day. The dose may be increased in 50 mg/day increments to achieve an effective dose, depending on individual clinical response and tolerability.

Children

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

Overdose

Symptoms

Signs and symptoms reported in overdose cases are generally consistent with an exaggeration of known pharmacological effects of the active substance, such as somnolence and sedation, tachycardia, hypotension, and anticholinergic effects. Overdose may lead to QT interval prolongation, seizures, status epilepticus, 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 Warnings and Precautions. Orthostatic Hypotension").

Treatment

There is no specific antidote for quetiapine. In cases of severe overdose, consider implementing appropriate supportive measures and intensive therapy, including maintaining airway patency, ensuring adequate oxygenation and ventilation, and monitoring and supporting cardiovascular function.

Based on published literature, patients presenting with delirium and agitation along with clear signs of anticholinergic syndrome may be treated with physostigmine at a dose of 1–2 mg under continuous ECG monitoring. However, this is not a recommended standard treatment for quetiapine overdose due to the potential negative effects of physostigmine on cardiac conduction. Physostigmine may be used only in the absence of ECG abnormalities. It should not be administered in cases of arrhythmias, any degree of heart block, or QRS complex widening.

Although prevention of absorption has not been studied in quetiapine overdose, gastric lavage may be considered in cases of severe overdose, but not later than one hour after drug ingestion. Administration of activated charcoal should also be considered.

Persistent hypotension in quetiapine overdose should be managed with appropriate interventions such as intravenous fluid administration and/or sympathomimetic agents. Adrenaline (epinephrine) and dopamine should be avoided, as stimulation of beta-adrenergic receptors may worsen hypotension in the presence of alpha-adrenergic blockade by quetiapine.

Close medical monitoring and observation should continue until full recovery.

In cases of overdose with prolonged-release quetiapine, delayed peak sedation and pulse rate, as well as a more prolonged recovery, may occur compared to immediate-release quetiapine.

Gastric bezoar formation has been reported in overdose with prolonged-release quetiapine; therefore, appropriate diagnostic imaging is recommended to guide further management. Standard gastric lavage may be ineffective due to the sticky, gum-like consistency of the mass.

Endoscopic removal of the pharmacobezoar has been successful in some cases.

Adverse Reactions

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

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

Blood and lymphatic system disorders: very common – decreased hemoglobin levels\22; common – leukopenia\1,28, decreased neutrophil count, increased eosinophil levels\27; uncommon – thrombocytopenia, anemia, decreased platelet count\13, neutropenia\1; rare – agranulocytosis\26.

Immune system disorders: uncommon – hypersensitivity (including skin allergic reactions); very rare – anaphylactic reaction\5.

Endocrine system disorders: common – hyperprolactinemia\15, decreased total T4\24, decreased free T4\24, decreased total T3\24, increased TSH\24; uncommon – decreased free T3\24, hypothyroidism\21; very rare – inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders: very common – increased serum triglycerides\10,30, increased total cholesterol (especially LDL-C)\11,30, decreased HDL-C\17,30, weight gain\8,30; common – increased appetite, increased blood glucose to hyperglycemic levels\6,30; uncommon – hyponatremia\19, diabetes mellitus\1,5, worsening of pre-existing diabetes; rare – metabolic syndrome\29.

Psychiatric disorders: common – unusual dreams and nightmares, suicidal thoughts and suicidal behavior\20; rare – sleepwalking and related phenomena such as sleep talking and eating disorders during sleep.

Nervous system disorders: very common – dizziness\4,16, somnolence\2,16, headache, extrapyramidal symptoms\1,21; common – dysarthria; uncommon – seizures\1, restless legs syndrome, tardive dyskinesia\1,5, loss of consciousness\4,16, confusional state.

Cardiac disorders: common – tachycardia\4, palpitations\23; uncommon – QT interval prolongation\1,12,18, bradycardia\32; frequency not known – cardiomyopathy, myocarditis.

Eye disorders: common – blurred vision.

Vascular disorders: common – orthostatic hypotension\4,16; rare – venous thromboembolism\1; frequency not known – stroke\33.

Renal and urinary disorders: uncommon – urinary retention.

Respiratory, thoracic and mediastinal disorders: common – dyspnea\23; uncommon – rhinitis.

Gastrointestinal disorders: very common – dry mouth; common – constipation, dyspepsia, vomiting\25; uncommon – dysphagia\7; rare – pancreatitis\1, intestinal obstruction/volvulus.

Hepatobiliary disorders: common – increased alanine aminotransferase (ALT) levels in serum\3, increased gamma-GT levels\3; uncommon – increased aspartate aminotransferase (AST) levels\3 in serum; rare – jaundice\5, hepatitis.

Skin and subcutaneous tissue disorders: very rare – angioedema\5, Stevens-Johnson syndrome\5; frequency not known – erythema multiforme, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS), cutaneous vasculitis.

Musculoskeletal and connective tissue disorders: very rare – rhabdomyolysis.

Pregnancy, puerperium and perinatal conditions: frequency not known – drug withdrawal syndrome in newborns\31.

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

General disorders and administration site conditions: very common – withdrawal symptoms (upon discontinuation)\1,9; common – mild asthenia, peripheral edema, irritability, fever; rare – neuroleptic malignant syndrome\1, hypothermia.

Investigations: rare – increased blood creatine phosphokinase levels\14.

(1) See section "Special warnings and precautions for use".

(2) Somnolence usually occurs within the first 2 weeks of treatment and usually resolves with continued quetiapine use.

(3) Asymptomatic increases (shift from normal to > 3 × ULN at any time) in serum transaminases (ALT, AST) or gamma-GT levels have been observed in some patients receiving quetiapine. These increases are usually reversible with continued quetiapine treatment.

(4) Like other antipsychotic drugs that block alpha1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension accompanied by dizziness, tachycardia, and in some patients, loss of consciousness, especially during initial dose titration (see section "Special warnings and precautions for use").

(5) The frequency count for these adverse reactions was based only on post-marketing data from the use of quetiapine 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) 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 compared to baseline. Occurs predominantly during the first weeks of therapy in adults.

(9) In short-term placebo-controlled monotherapy clinical trials assessing discontinuation symptoms, the most commonly observed withdrawal symptoms were insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions significantly decreased within 1 week after stopping treatment.

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

(11) Cholesterol levels ≥ 240 mg/dL (≥ 6.2064 mmol/L) (patients ≥ 18 years) or ≥ 200 mg/dL (≥ 5.172 mmol/L) (patients < 18 years) on at least one occasion. Increases in LDL-C ≥ 30 mg/dL (≥ 0.769 mmol/L) were observed very commonly. The mean value in patients with such increase was 41.7 mg/dL (≥ 1.07 mmol/L).

(12) See text below.

(13) Platelet count ≤ 100 × 10\9/L on at least one occasion.

(14) According to clinical trial adverse reaction reports, increased blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.

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

(16) May lead to falls.

(17) HDL-C levels: < 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 in whom QTc interval changed from < 450 ms to ≥ 450 ms with an increase of ≥ 30 ms. In placebo-controlled quetiapine studies, the mean change and number of patients with a shift to a clinically significant level were similar in quetiapine and placebo groups.

(19) Shift from > 132 mmol/L to ≤ 132 mmol/L on at least one occasion.

(20) Cases of suicidal thoughts and suicidal behavior have been reported during quetiapine therapy or in the early period after discontinuation (see sections "Pharmacological properties" and "Special warnings and precautions for use").

(21) See section "Pharmacodynamics".

(22) Decrease in hemoglobin to ≤ 13 g/dL (8.07 mmol/L) in males, ≤ 12 g/dL (7.45 mmol/L) in females on at least one occasion occurred in 11% of patients treated with quetiapine across all studies, including open-label extension studies. The mean maximum decrease in hemoglobin at any time in these patients was –1.50 g/dL.

(23) These reports often occurred in the context of tachycardia, dizziness, orthostatic hypotension, and/or concomitant cardiac/respiratory disorders.

(24) Based on deviations from normal baseline levels to potentially clinically significant values at any time after the start of 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 frequency of vomiting in elderly patients (≥ 65 years).

(26) Based on deviations in neutrophil count from > 1.5 × 10\9/L initially to < 0.5 × 10\9/L at any time during treatment and on patients with severe neutropenia (< 0.5 × 10\9/L) and infection across all quetiapine clinical trials (see section "Special warnings and precautions for use").

(27) Based on deviations from normal baseline levels to potentially clinically significant values at any time after the start of all studies. Eosinophil count deviation was > 1 × 10\9 cells/L at any time.

(28) Based on deviations from normal baseline levels to potentially clinically significant values at any time after the start of all studies. Leukocyte count deviation was ≤ 3 × 10\9 cells/L at any time.

(29) Based on adverse reaction reports of metabolic syndrome in all quetiapine clinical trials.

(30) During clinical trials, some patients experienced worsening of more than one of the following metabolic factors: body weight, glucose, and blood lipids (see section "Special warnings and precautions for use").

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

(32) May occur during or shortly after initiation of therapy and may be associated with arterial hypotension and/or loss of consciousness. Frequency is based on adverse reaction reports of bradycardia and related events in all quetiapine clinical trials.

(33) Based on one retrospective non-randomized epidemiological study.

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

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.

Children

The adverse reactions listed above observed in adults also occur in children and adolescents. Below are adverse reactions with higher frequency in this age group (10–17 years) or not observed in adult patients.

Adverse reactions are listed according to frequency of occurrence using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10,000).

Endocrine disorders: very common – increased prolactin levels\1.

Metabolism and nutrition disorders: very common – increased appetite.

Nervous system disorders: very common – extrapyramidal symptoms\3,4; common – loss of consciousness.

Vascular disorders: very common – increased blood pressure\2.

Respiratory, thoracic and mediastinal disorders: common – rhinitis.

Gastrointestinal disorders: very common – vomiting.

General disorders and administration site conditions: common – irritability\3.

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

2. Based on deviations above clinically significant thresholds (adapted National Institute for Health criteria) or increases > 20 mmHg for systolic or > 10 mmHg for diastolic blood pressure at any time, from short-term (3–6 weeks) placebo-controlled trials in children and adolescents.

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

4. See section "Pharmacodynamics".

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, out of reach of children. No special storage conditions required.

Packaging.

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

Prescription status. Prescription only.

Manufacturer

FARMATEN INTERNATIONAL S.A.

Manufacturer's address and location of operations

Industrial Park Sapes, Prefecture of Rodopi, Block No. 5, Rodopi 69300, Greece.

Marketing Authorization Holder

TOV "ASINO UKRAINE".

Address of Marketing Authorization Holder

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

For adverse effects and questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of TOV "ASINO UKRAINE" at:

8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.