Quetiapax® sr

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

Composition:

Active substance: quetiapine;

One prolonged-release tablet contains 150 mg, 200 mg, or 300 mg of quetiapine (as quetiapine fumarate);

Excipients: hypromellose, lactose monohydrate, microcrystalline cellulose, sodium hydrogen phosphate dihydrate, magnesium stearate;

Film coating: Opadry II HP White (a mixture of polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), polyethylene glycol 3000, and talc), iron oxide red (E 172) (for 150 mg tablets), iron oxide yellow (E 172) (for 150 mg, 200 mg, and 300 mg tablets).

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

• 150 mg prolonged-release tablets: film-coated, pink-orange in color, round, biconvex, with beveled edges;
• 200 mg prolonged-release tablets: film-coated, yellow-brown in color, oval, biconvex;
• 300 mg prolonged-release tablets: film-coated, pale brownish-yellow in color, capsule-shaped, biconvex.

Pharmacotherapeutic group. Antipsychotic agents. Quetiapine.

ATC code N05A H04.

Pharmacological properties.

Pharmacodynamics.

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 receptors relative to D2 receptors, is considered to contribute to the clinical antipsychotic effects of Quetiapine SR and to its low propensity for extrapyramidal side effects compared with typical antipsychotic agents.

Quetiapine has no affinity for the norepinephrine transporter (NET) and low affinity for serotonin 5HT1A receptors, whereas norquetiapine has high affinity for both. Inhibition of norquetiapine (NET) and partial agonist activity at 5HT1A receptors may contribute to the therapeutic efficacy of Quetiapine SR as an antidepressant. Quetiapine and norquetiapine have high affinity for histamine receptors and alpha1-adrenergic receptors, and moderate affinity for alpha2-adrenergic receptors. Quetiapine has low or no affinity for muscarinic receptors, whereas norquetiapine has moderate to high affinity for several subtypes of muscarinic receptors.

Pharmacodynamic effects

Quetiapine is active in tests of antipsychotic activity, such as conditioned avoidance response. It also blocks the effects of dopamine agonists, measured either behaviorally or electrophysiologically, and increases concentrations of dopamine metabolites, a neurochemical index of D2 receptor blockade.

Pharmacokinetics.

Absorption

Quetiapine is well absorbed after oral administration. Peak plasma concentrations (Tmax) of quetiapine and norquetiapine are reached approximately 6 hours after administration of Quetiapine SR. At steady state, the peak molar concentration of the active metabolite norquetiapine is 35% of that of quetiapine.

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

In studies evaluating the effect of food on quetiapine bioavailability, high-fat meals were shown to cause statistically significant increases in Cmax and AUC of Quetiapine SR by approximately 50% and 20%, respectively. A greater effect of high-fat meals on the drug cannot be ruled out. Light meals have no significant effect on Cmax and AUC of quetiapine. Quetiapine SR is recommended to be taken once daily without food.

Distribution

Approximately 83% of quetiapine is bound to plasma proteins.

Metabolism

Quetiapine is extensively metabolized in the liver. Studies using radiolabeled quetiapine have shown that less than 5% of quetiapine is excreted unchanged in urine or feces.

Elimination

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

Special populations

Gender

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

Elderly

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

Renal impairment

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), although individual clearance values remain within the range observed in healthy volunteers.

Hepatic impairment

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").

Clinical characteristics.

Indications.

Treatment of schizophrenia.

Treatment of bipolar disorders, including:

• moderate to severe manic episodes associated with bipolar disorders;
• major depressive episodes associated with bipolar disorders.

Prevention of recurrence in patients with bipolar disorders whose manic or depressive episodes have been treated with quetiapine.

As adjunctive therapy for major depressive episodes in patients with major depressive disorder (MDD) who have had a suboptimal response to antidepressant monotherapy. Prior to initiating therapy, the physician must carefully review the safety profile of Quentiax® SR.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

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, Quentiax® SR should be used with caution in combination with other centrally acting agents and with alcohol.

Caution is advised when administering quetiapine concomitantly with medicinal products having anticholinergic (muscarinic) effects (see section "Special precautions").

Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for quetiapine metabolism. In interaction studies in healthy volunteers, coadministration 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 study assessing the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant administration of carbamazepine significantly increased quetiapine clearance. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to approximately 13% of exposure observed with quetiapine alone, although a greater effect was observed in some patients. Due to this interaction, plasma concentrations of quetiapine may decrease, potentially affecting the efficacy of Quentiax® SR.

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

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).

Coadministration with antipsychotics such as risperidone or haloperidol did not cause significant changes in quetiapine pharmacokinetics. Concomitant administration of quetiapine and thioridazine increased quetiapine clearance by approximately 70%.

Pharmacokinetics of quetiapine were not altered when administered concomitantly with cimetidine.

The pharmacokinetics of lithium were not altered by concomitant administration with quetiapine.

In a 6-week randomized study comparing lithium plus Quentiax® SR versus placebo plus Quentiax® SR in adults with acute mania, an increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain was observed in the lithium add-on group compared to the placebo add-on group (see section "Pharmacodynamic properties").

No clinically significant changes in the pharmacokinetics of sodium valproate or quetiapine were observed with concomitant administration. In a retrospective study involving children and adolescents receiving sodium valproate, quetiapine, or a combination of both, a higher 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 alter electrolyte balance or prolong the QT interval.

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

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

Special precautions for use.

Since Quetiapex® SR is indicated for the treatment of schizophrenia, bipolar disorder, and adjunctive treatment of depressive episodes in patients with MDD, the safety profile of the drug should be carefully considered based on the specific diagnosis established for the 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 monotherapy with the drug in adult patients have been studied (see section "Pharmacodynamics").

Children

Quetiapex® is not recommended for use in children due to the 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 for adults, the frequency of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, and extrapyramidal symptoms), and one event previously not observed in studies involving adult patients has been identified (increased blood pressure). Additionally, changes in thyroid function parameters have been observed in children and adolescents.

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

During studies involving pediatric and adolescent patients, treatment with quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section "Adverse reactions").

Suicide/suicidal thoughts or clinical worsening

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

Furthermore, the potential risk of suicide-related events after abrupt discontinuation of quetiapine treatment should be considered due to known risk factors associated with the condition being treated.

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

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

Patients with a history of suicide-related events or who exhibit a significant level of suicidal thinking prior to the start of therapy have a higher risk of developing suicidal thoughts or suicide attempts 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 in patients under 25 years of age.

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

In short-term placebo-controlled trials involving patients with major depressive episodes in bipolar disorders, 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 younger patients (under 25 years of age) was 2.1% (3/144) in the group receiving quetiapine and 1.3% (1/75) in the placebo group. A population-based retrospective study of quetiapine use in the treatment of 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.

Drowsiness and dizziness

Treatment with quetiapine is associated with drowsiness 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 predominantly mild to moderate in intensity. For patients with bipolar depression and patients with depressive episodes in MDD who experience drowsiness, monitoring may be necessary for 2 weeks after the onset of drowsiness or until symptoms resolve, or consideration may need to be given to discontinuing treatment.

Orthostatic hypotension

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

Cardiovascular diseases

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

Sleep apnea syndrome

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

Seizures

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

Extrapyramidal symptoms

In placebo-controlled trials, quetiapine was associated with an increased frequency of extrapyramidal symptoms 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 subjectively unpleasant or distressing restlessness and a need to move, often accompanied by an inability to sit or stand still. These phenomena are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may be harmful.

Tardive dyskinesia

If symptoms of tardive dyskinesia occur, consideration should be given to reducing the dose or discontinuing the use of Quetiapex® SR. Symptoms of tardive dyskinesia may worsen and 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® SR should be discontinued and appropriate treatment initiated.

Severe neutropenia and agranulocytosis

Severe neutropenia (neutrophil count <0.5×10⁹/L) has been observed in clinical trials of quetiapine. Most cases of severe neutropenia occurred within two months after the start of 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.

It is recommended to discontinue quetiapine treatment if the neutrophil count in the blood is <1.0×10⁹/L. Patients should be monitored for symptoms of infection and changes in neutrophil levels (until levels exceed 1.5×10⁹/L) (see section "Pharmacodynamic properties").

Anticholinergic (muscarinic) effects

Norquetiapine, an active metabolite of quetiapine, has moderate or high affinity for several subtypes of muscarinic receptors. This contributes to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used concomitantly at recommended doses with other drugs having anticholinergic effects 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 of or history of urinary retention, clinically significant benign prostatic hyperplasia, 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 reduce the effectiveness of quetiapine therapy. Treatment with Quetiapex® SR in patients receiving a hepatic enzyme inducer should only be initiated if the physician considers that the benefit of using Quetiapex® SR outweighs 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 and/or development or exacerbation of diabetes mellitus have sometimes been associated with ketoacidosis or coma, including several cases with fatal outcomes (see section "Adverse reactions"). Several cases have been reported with prior weight gain, which may be a predisposing factor. Appropriate clinical monitoring should be performed according to existing guidelines for the use of antipsychotic agents. Patients treated with any antipsychotic drugs, including quetiapine, should be monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes or risk factors for diabetes require regular monitoring for worsening glucose control. The body weight of such patients should be continuously monitored.

Lipids

Elevated levels of triglycerides, LDL cholesterol, and total cholesterol, and decreased levels of HDL cholesterol have been observed in clinical trials of quetiapine (see section "Adverse reactions"). Appropriate treatment should be prescribed when lipid levels change.

Metabolic risk

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

Prolongation of QT interval

In clinical trials and during use according to the medical instructions, quetiapine did not cause a sustained increase in absolute QT intervals. During the post-marketing period, QT interval prolongation has been observed with quetiapine use at therapeutic doses (see section "Adverse reactions") and in cases of overdose (see section "Overdose"). As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases or patients with a family history of prolonged QT interval. Caution should also be exercised when prescribing quetiapine with other medicinal products known to prolong the QT interval, or when used concomitantly with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, 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 skin reactions accompanied by eosinophilia and systemic manifestations (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 the start of quetiapine treatment; some DRESS reactions occurred within 6 weeks after the start of quetiapine treatment. If signs and symptoms indicating these severe skin reactions appear, quetiapine should be immediately discontinued and alternative treatment methods 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® SR is not recommended for the treatment of psychosis associated with dementia.

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

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

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

A population-based retrospective study in the treatment of patients with MDD showed an increased risk of fatal outcome during quetiapine use in patients over 65 years of age. This association was absent when patients with parkinsonism were excluded from the analysis. Caution should be exercised when prescribing quetiapine to this patient group.

Dysphagia

Dysphagia has been observed during 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 during the use of quetiapine (see section "Adverse reactions"). These reports include information about fatal outcomes in patients who have a higher risk of developing intestinal obstruction, including patients receiving concomitantly multiple drugs that reduce intestinal peristalsis and/or drugs for which there may have been no reported information about causing constipation. Treatment of patients with intestinal obstruction/volvulus should be conducted under close supervision and with immediate medical assistance.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been observed during the use of neuroleptic agents. Since patients taking neuroleptics often have acquired risk factors for VTE, all possible risk factors for the development of VTE should be identified before and during quetiapine therapy, and preventive measures should be taken.

Pancreatitis

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

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 appropriateness of quetiapine use should be re-evaluated in patients suspected of having cardiomyopathy or myocarditis.

Serotonin syndrome

Concomitant use of Quetiapex® SR 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, which can be potentially life-threatening (see "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic agents is clinically justified, close 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; however, combination therapy was well tolerated (see sections "Adverse reactions" and "Pharmacodynamic properties"). These data showed an additive effect by the third week of treatment.

Irrational use and abuse

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

Lactose

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

Each prolonged-release tablet of 150 mg contains 37.57 mg of lactose.

Each prolonged-release tablet of 200 mg contains 50.09 mg of lactose.

Each prolonged-release tablet of 300 mg contains 75.15 mg of lactose.

Sodium

The prolonged-release 150 mg tablet contains 14.53 mg of sodium.

The prolonged-release 200 mg tablet contains 19.38 mg of sodium.

Doses of more than 1 tablet contain over 23 mg (1 mmol) of sodium. This should be considered for patients on a sodium-controlled diet.

Each prolonged-release tablet of 300 mg contains 29.06 mg of sodium.

This should be considered for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding

The safety and efficacy of quetiapine use for the treatment of pregnant women have not been established. Currently, there is no evidence of negative effects obtained from animal studies. Possible effects on fetal visual organs have not been studied. According to information from several pregnancies during which quetiapine was used, neonatal withdrawal symptoms have been reported in newborns. Therefore, Quetiapex® SR may be prescribed during pregnancy only if the expected benefit justifies the potential risk. Newborns whose mothers took quetiapine during pregnancy have exhibited withdrawal symptoms.

Published data indicate that quetiapine penetrates into human breast milk, although the extent of this penetration is unknown. Women who are breastfeeding are advised to discontinue breastfeeding during quetiapine treatment.

Newborns whose mothers took antipsychotic drugs (including quetiapine) during the third trimester have a risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration. Adverse reactions observed include agitation, arterial hypertension, hypotension, tremor, drowsiness, respiratory disorders, or feeding disorders. Thus, newborns should be under close supervision.

Ability to affect reaction speed when driving or operating machinery

Since the drug primarily acts on the central nervous system, quetiapine may negatively affect mental performance. Therefore, patients are not recommended to drive or operate machinery until their individual response to the drug is determined.

Dosage and Administration

Different dosing regimens exist for each indication. It is important to ensure that the patient receives a dose appropriate to their condition.

Quetiapine SR should be administered once daily on an empty stomach. Tablets should be swallowed whole and must not be split, chewed, or crushed.

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

Quetiapine SR should be taken at least 1 hour before a meal. The initial daily dose is 300 mg on Day 1 and 600 mg on Day 2. The recommended daily dose is 600 mg; however, if clinically justified, the dose may be increased up to 800 mg per day. The dose should be adjusted within the effective dose range of 400–800 mg per day, depending on clinical response and tolerability. Dose adjustment is not required for maintenance therapy in schizophrenia.

Treatment of depressive episodes in bipolar disorder

Quetiapine SR should be taken at bedtime. The total daily dose during the first four days of treatment is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3), and 300 mg (Day 4). The recommended daily dose is 300 mg. Clinical studies did not show additional benefit with the 600 mg dose compared to the 300 mg dose (see section "Pharmacological properties"). The 600 mg dose may be effective in some patients. Doses above 300 mg should be prescribed only by physicians experienced in the treatment of bipolar disorder. Clinical studies suggest that for individual patients experiencing tolerability issues, 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 should continue therapy with Quetiapine SR at the same bedtime dose. The dose of Quetiapine SR 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

Quetiapine SR 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 therapy studies (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine), antidepressant effects were observed at doses of 150 and 300 mg/day, and at 50 mg/day in a short-term monotherapy study. The risk of adverse reactions increases with higher doses. Therefore, physicians should ensure the use of the lowest effective dose, starting at 50 mg/day. Any need to increase the dose from 150 to 300 mg/day should be based on individual patient assessment.

Switching from immediate-release Quetiapine

For easier dosing, patients previously treated with immediate-release Quetiapine tablets may be switched to Quetiapine SR at an equivalent total daily dose administered once daily. Dose titration may be necessary to maintain clinical response.

Elderly patients

As with other antipsychotics and antidepressants, Quetiapine SR should be used with caution in elderly patients, especially during initial treatment and dose titration. Slower dose titration may be required, and the daily therapeutic dose may be lower than in younger patients. The mean plasma clearance of quetiapine is reduced by 30–50% in elderly individuals compared to younger patients. Treatment should begin at a dose of 50 mg/day. The dose may be gradually increased by 50 mg/day to achieve an effective dose based on individual clinical response and tolerability. For elderly patients with depressive episodes in MDD, treatment should start at 50 mg/day on Days 1–3, increasing to 100 mg/day on Day 4 and 150 mg/day on Day 8. The lowest effective dose, starting at 50 mg/day, should be used. If, based on individual patient assessment, an increase to 300 mg/day is required, this should not occur earlier than 22 days after starting treatment.

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

Renal impairment

Dose adjustment is not required in patients with renal impairment.

Hepatic impairment

Quetiapine is extensively metabolized in the liver. Therefore, Quetiapine SR should be used with caution in patients with known hepatic impairment, particularly during initial dose titration. Treatment should begin 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 SR 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 with overdose are consistent with an exaggeration of known pharmacological effects of the active substance, such as somnolence and sedation, tachycardia, hypotension, and anticholinergic effects. Survival has been reported following acute overdose of up to 30 g of quetiapine. Most patients with overdose either reported no adverse events or fully recovered after such events. A fatal outcome was reported in a clinical trial following an overdose of 13.6 g of quetiapine. From post-marketing experience, reports of quetiapine overdose as monotherapy leading to death, coma, or QT prolongation have been very rare. Overdose may result in QT prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, disorientation, delirium and/or agitation, coma, and death. Additionally, the following events have been reported with quetiapine monotherapy overdose: QT prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation. Patients with pre-existing severe cardiovascular disease may be at increased risk of overdose effects (see section "Special precautions").

Treatment

There is no specific antidote for quetiapine. In cases of severe overdose, appropriate supportive measures and intensive therapy should be considered, including maintaining airway patency, ensuring adequate oxygenation and ventilation, and monitoring and supporting cardiovascular function. Published reports describe reversal of serious CNS effects, including coma and delirium, by intravenous administration of physostigmine (1–2 mg) under continuous ECG monitoring. This is not a recommendation for standard treatment due to the potential negative effects of physostigmine on cardiac conduction. Physostigmine may be used only if no ECG abnormalities are present. Physostigmine should not be used in the presence of arrhythmias, any degree of heart block, or QRS complex widening.

In cases of persistent hypotension following quetiapine overdose, appropriate measures such as intravenous fluid administration and/or sympathomimetics should be taken (adrenaline and dopamine should be avoided, as beta-adrenergic stimulation may worsen hypotension in the context of alpha-adrenergic blockade caused by quetiapine).

Since prevention of absorption has not been studied in overdose, gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal with a laxative should be considered.

Formation of bezoars in the stomach has been reported following overdose with extended-release quetiapine; therefore, appropriate diagnostic imaging is recommended to determine further management. Standard gastric lavage may be ineffective in removing the bezoar due to its sticky, gum-like consistency. In some cases, endoscopic removal of the pharmacobezoar has been successful.

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

Adverse Reactions

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

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

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

1. See section "Special precautions".

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

3. Asymptomatic elevations (deviations from normal to >3×ULN at any time) of transaminase levels (ALT, AST) or gamma-GT (glutamyl transferase) 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 initial dose titration period (see section "Special precautions").

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

6. Fasting blood glucose level ≥126 mg/dl (≥7.0 mmol/l) or postprandial blood glucose level ≥200 mg/dl (≥11.1 mmol/l) 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 markedly 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. Increase in LDL cholesterol ≥30 mg/dl (≥0.769 mmol/l) was very common. The mean value among patients with such LDL cholesterol increase 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, elevated 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 men; >30 µg/l (>1304.34 pmol/l) in women – at any time.

16. May lead to falls.

17. HDL cholesterol <40 mg/dl (1.025 mmol/l) in men; <50 mg/dl (1.282 mmol/l) in women 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 at one examination.

20. Cases of suicidal thoughts and suicidal behaviour were 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 men, ≤12 g/dl (7.45 mmol/l) in women at least at one examination was observed in 11% of patients treated with quetiapine across all studies, including open-label studies. 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×ULN (pmol/l), and TSH deviation was >5 mU/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 adverse reaction reports of metabolic syndrome from all clinical trials of quetiapine.

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

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

32. May occur during or shortly after initiation of therapy and may be associated with hypotension and/or syncope. 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 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 be considered in children and adolescents. Table 2 summarizes ADRs occurring at a higher frequency in paediatric and adolescent patients (10–17 years) compared to adults, or ADRs not observed in the adult patient group.

Table 2. ADRs in children and adolescents associated with quetiapine treatment that occur more frequently than in adults or not observed in the adult patient group.

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).

1 Prolactin 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 >100 µg/L.

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

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

4 See section "Pharmacodynamics".

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Keep in the original packaging to protect from moisture. The medicinal product does not require special storage temperature conditions.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 6 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

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

Manufacturer's address and location of business operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.