Seroquel xr: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Seroquel XR (Seroquel XR)

Composition:

Active substance:

50 mg tablets: 1 tablet contains 57.56 mg of quetiapine fumarate, equivalent to 50 mg of quetiapine;

200 mg tablets: 1 tablet contains 230.26 mg of quetiapine fumarate, equivalent to 200 mg of quetiapine;

300 mg tablets: 1 tablet contains 345.38 mg of quetiapine fumarate, equivalent to 300 mg of quetiapine;

400 mg tablets: 1 tablet contains 460.50 mg of quetiapine fumarate, equivalent to 400 mg of quetiapine;

Excipients:

lactose monohydrate; microcrystalline cellulose; sodium citrate; magnesium stearate; hypromellose 2208; hypromellose 2910; polyethylene glycol 400; titanium dioxide (E 171);

for 50 mg, 200 mg and 300 mg tablets – iron oxide yellow (E 172);

for 50 mg tablets – iron oxide red (E 172).

Pharmaceutical form. Prolonged-release film-coated tablets.

Main physicochemical properties:

50 mg:

capsule-shaped, biconvex, peach-colored film-coated tablet, engraved with ‘XR 50’ on one side and smooth on the other;

200 mg:

capsule-shaped, biconvex, yellow film-coated tablet, engraved with ‘XR 200’ on one side and smooth on the other;

300 mg:

capsule-shaped, biconvex, light yellow film-coated tablet, engraved with ‘XR 300’ on one side and smooth on the other;

400 mg:

capsule-shaped, biconvex, white film-coated tablet, engraved with ‘XR 400’ on one side and smooth on the other.

Pharmacotherapeutic group. Agents acting on the nervous system. Antipsychotics. 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 receptors than for D2 receptors, is considered to contribute to the clinical antipsychotic effects and low propensity for extrapyramidal side effects with the use of the medicinal product Seroquel XR, compared to typical antipsychotic medicinal products.

Quetiapine has no affinity for the norepinephrine transporter and has low affinity for serotonin 5HT1A receptors, whereas norquetiapine has high affinity for both. Inhibition by norquetiapine, as well as partial agonist activity at 5HT1A receptors, may contribute to the therapeutic efficacy of Seroquel XR as an antidepressant. Quetiapine and norquetiapine have high affinity for histaminergic 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, as 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 Seroquel XR. Peak molar concentrations of the active metabolite norquetiapine at steady state are 35% of those of quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear and dose-proportional up to doses of 800 mg inclusive when administered once daily. When comparing equivalent total daily doses of Seroquel XR administered once daily and immediate-release Seroquel (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 with Seroquel XR. When comparing Seroquel XR and immediate-release Seroquel, the AUC of the metabolite norquetiapine is 18% lower with Seroquel XR.

In a study investigating the effect of food on the bioavailability of quetiapine, high-fat meals were shown to cause statistically significant increases in Cmax and AUC of approximately 50% and 20%, respectively, with Seroquel XR. 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 have no significant effect on Cmax and AUC of quetiapine. Seroquel XR 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. 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 average molar fraction of unchanged quetiapine and the active metabolite norquetiapine is excreted in urine.

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), although individual clearance values remain 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 of quetiapine are expected in patients with hepatic impairment. Dose adjustment may be required for such patients.

Clinical characteristics.

Indications.

Seroquel XR is indicated for the treatment of:

Schizophrenia, including prevention of recurrence of relapse in patients with stable schizophrenia who have been maintained on supportive therapy with the medicinal product Seroquel XR.
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 disease relapse in patients with bipolar disorder who have manic or depressive episodes effectively managed with the medicinal product Seroquel XR.
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, the physician must carefully consider the safety profile of Seroquel XR.

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.

Due to the primary effects of quetiapine on the central nervous system, quetiapine 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 (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as the risk of developing serotonin syndrome, a potentially life-threatening condition, may be increased (see section "Special precautions for use").

Caution should be exercised when treating patients receiving 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 an interaction study 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 therapy.

In a multiple-dose study assessing the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a known hepatic enzyme inducer), concomitant use of carbamazepine significantly increased quetiapine clearance. This increased clearance reduced systemic exposure to quetiapine (measured as AUC) to approximately 13% of the exposure observed with quetiapine alone, although a greater effect was observed in some patients. Due to this interaction, lower plasma concentrations of quetiapine may occur, potentially affecting the efficacy of Seroquel XR 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 if, in the physician’s opinion, the benefit of quetiapine outweighs the risks associated with discontinuation of the enzyme inducer. Gradual substitution of the inducer and, if necessary, replacement with a non-inducer (e.g., sodium valproate) is important—see section "Special precautions for use".

The pharmacokinetics of quetiapine are not significantly altered by concomitant administration of antidepressants such as imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor).

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

The pharmacokinetics of quetiapine were not altered after co-administration with cimetidine.

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

In a 6-week randomized study comparing the combination of lithium and Seroquel XR versus placebo and Seroquel XR in adult patients with acute mania, the group receiving lithium showed an increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain compared to the placebo group (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 the monotherapy groups.

Formal interaction studies with the most commonly used cardiovascular medicinal products have not been conducted. Caution should be exercised when using quetiapine concomitantly with medicinal products that alter electrolyte balance or prolong the QT interval.

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

Special precautions for use.

Since Seroquel XR 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 should be carefully considered with regard to the specific diagnosis and dose prescribed to the individual patient.

Children

Seroquel XR is not recommended for use in children due to lack of data supporting its use in this age group. Clinical studies of quetiapine have shown that, in addition to the known safety profile established in adults, the frequency of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, and extrapyramidal symptoms), and one event not previously observed in studies involving adult patients has been identified (elevated blood pressure). In addition, changes in thyroid function parameters have been observed in children and adolescents.

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

During placebo-controlled clinical trials of Seroquel XR involving pediatric and adolescent patients, treatment with quetiapine was associated with an increased incidence 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 is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal events and manifestations). This risk persists until significant/definitive 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 manifestations following abrupt discontinuation of quetiapine treatment due to the presence of 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 manifestations. At the same time, these conditions may coexist with major depressive episodes. Therefore, when treating patients with other psychiatric disorders, the same precautions should be taken as when treating patients with major depressive episodes.

It is known that patients with a history of suicidal events and manifestations or those who demonstrate a significant level of suicidal ideation prior to the start of therapy have a higher risk of suicidal thoughts or suicide attempts and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressant use compared to placebo in patients under 25 years of age.

Close monitoring of patients, particularly those at high risk, should accompany pharmacological treatment, especially in the early stages of treatment and following dose changes. Patients (and caregivers) should be warned 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, a higher risk of suicidal events and manifestations 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 MDD, the frequency of suicidal events and manifestations in young 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 analysis of quetiapine use in the treatment of patients with major depressive disorder revealed an increased risk of self-harm and suicide in patients aged 24 to 64 years without a history of self-harm during quetiapine use in combination 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 monitored regularly throughout the treatment course. Worsening of these parameters should be managed considering clinical appropriateness.

Extrapyramidal symptoms

In placebo-controlled clinical trials involving adult patients, quetiapine use was associated with an increased frequency of extrapyramidal symptoms compared to placebo in patients treated for major depressive episodes in bipolar disorder and major depressive disorder.

Quetiapine use has been associated with the development of akathisia, characterized by subjectively unpleasant or stress-inducing 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. For patients who develop these symptoms, dose escalation may be harmful.

Tardive dyskinesia

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

Somnolence and dizziness

Treatment with quetiapine has been associated with somnolence and similar symptoms such as sedation. In clinical trials of patients with bipolar depression and major depressive disorder, such symptoms usually occurred within the first 3 days of treatment and were predominantly mild to moderate in intensity. Patients who experience severe somnolence may require more frequent monitoring for at least 2 weeks after the onset of somnolence or until symptoms resolve, and discontinuation of treatment may need to be considered.

Orthostatic hypotension

Treatment with quetiapine has been associated with orthostatic hypotension and associated dizziness, which, like somnolence, usually occur during the initial dose titration period. This may lead to an increased frequency of accidental injuries (falls), especially in elderly patients. Therefore, patients should be advised to be cautious until they become accustomed to the possible effects of the medicinal product.

Quetiapine should be used with caution in patients with established cardiovascular diseases, cerebrovascular diseases, or other conditions that may lead to hypotension. Consideration should be given to reducing the dose or prolonging dose titration 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. Quetiapine should be used with caution in patients who are concurrently receiving central nervous system depressants, have a history of sleep apnea, or are at risk. This includes, in particular, patients with excess weight/obesity or male patients.

Seizures

Controlled clinical trials did not show a difference 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 treatment with other antipsychotic medicinal products, quetiapine should be used cautiously in the treatment of patients with a history of epileptic seizures (see section "Adverse reactions").

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome has been associated with treatment with antipsychotic medicinal products, including quetiapine. Clinical manifestations include hyperthermia, changes in 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 Seroquel XR and other serotonergic medicinal products, such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome, a potentially life-threatening condition (see section "Interaction with other medicinal products and other types of interactions").

If concomitant treatment with other serotonergic medicinal products is clinically justified, careful monitoring of the patient is recommended, 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. Possible risk factors for neutropenia include pre-existing low white blood cell (WBC) count and drug-induced neutropenia in the patient's 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. Patients should be monitored for signs and symptoms of infection and neutrophil counts (until levels exceed 1.5 × 10⁹/L).

Neutropenia should be considered in patients with existing infection and fever, especially in the absence of obvious predisposing factor(s), and managed considering clinical appropriateness.

Patients should be advised to immediately report signs/symptoms indicating agranulocytosis or infection (such as fever, weakness, lethargy, or sore throat) at any time during treatment with Seroquel XR. Such patients should promptly undergo white blood cell 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 affects the PRLZ, reflecting anticholinergic effects when quetiapine is used at recommended doses, concomitantly with other anticholinergic medicinal products, or in cases of overdose. Quetiapine should be used with caution in patients receiving medicinal products with anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with a current diagnosis or history of urinary retention, clinically significant prostate hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure, or closed-angle glaucoma.

Interactions

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

Concomitant use of quetiapine and a strong hepatic enzyme inducer, such as carbamazepine or phenytoin, significantly reduces quetiapine plasma concentrations, which may affect the efficacy of quetiapine therapy. In patients receiving a hepatic enzyme inducer, quetiapine treatment should only be initiated if, in the physician's opinion, the benefit of prescribing quetiapine outweighs the risks of discontinuing the hepatic enzyme inducer. It is important to perform any replacement gradually, and if necessary, replace the inducer with a non-inducer (e.g., sodium valproate).

Body weight

Weight gain has been reported in patients treated with quetiapine, which should be monitored and managed considering clinical appropriateness according to recommendations for antipsychotic medicinal products.

Hyperglycemia

Hyperglycemia and/or development or exacerbation of diabetes mellitus, in some cases associated with ketoacidosis or coma, occurred rarely, including several cases with fatal outcomes. In some cases, prior weight gain was reported, which may be a predisposing factor for hyperglycemia and/or development or exacerbation of diabetes mellitus. Appropriate clinical monitoring is advisable according to recommendations for antipsychotic medicinal products. Patients treated with any antipsychotic medicinal products, including quetiapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or existing risk factors for developing diabetes mellitus should be regularly examined for worsening glucose control. Body weight should be monitored regularly.

Lipids

Elevations in triglycerides, LDL-C, and total cholesterol, as well as reductions in HDL-C cholesterol, were observed in clinical trials of quetiapine. Lipid level changes should be managed considering clinical appropriateness.

QT interval prolongation

During clinical trials and when used according to the instructions for medical use, quetiapine administration was not associated with sustained absolute QT interval prolongation. In the post-marketing period, QT interval prolongation has been observed with quetiapine use at therapeutic doses and in cases of overdose. As with other antipsychotic medicinal products, quetiapine should be used cautiously in patients with cardiovascular diseases or a family history of QT interval prolongation. Caution should also be exercised when prescribing quetiapine with medicinal products that prolong the QT interval, 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 interactions").

Cardiomyopathy and myocarditis

Cases of cardiomyopathy and myocarditis have been reported during clinical trials and post-marketing use (see section "Adverse reactions"). Discontinuation of quetiapine should be considered in patients suspected of having cardiomyopathy or myocarditis.

Severe skin reactions

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

SCAR typically present with one or more of the following symptoms: significant 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 4 weeks after starting quetiapine therapy, and some cases of DRESS syndrome were reported within 6 weeks after starting quetiapine therapy. If signs and symptoms suggestive of such severe skin reactions occur, quetiapine should be immediately discontinued and alternative treatment considered.

Discontinuation of the medicinal product

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

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 patients with dementia, use of some atypical antipsychotic medicinal products was associated with approximately a threefold higher risk of cardiovascular adverse events. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or other patient categories. Quetiapine should be used with caution in patients with risk factors for stroke.

According to meta-analysis data of atypical antipsychotics, elderly patients suffering from psychosis associated with dementia are at increased risk of mortality compared to the placebo group. According to data from two 10-week placebo-controlled trials of quetiapine in the same patient category (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. In these trials, patients died from various causes expected for this category.

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

A population-based retrospective analysis of quetiapine use in the treatment of patients with MDD showed an increased risk of death during quetiapine use in patients over 65 years of age. These data were not confirmed when patients with Parkinson's disease were excluded from the analysis results. Caution should be exercised if quetiapine is prescribed to elderly patients with PD.

Dysphagia

Cases of dysphagia have been reported with quetiapine use. Quetiapine should be used with caution in patients at risk of aspiration pneumonia.

Constipation and intestinal obstruction

Constipation is a risk factor for the development of intestinal obstruction. Cases of constipation and obstruction have been reported with quetiapine use, including fatal cases in patients at higher risk of intestinal obstruction, including those receiving multiple medicinal products that reduce intestinal peristalsis and/or medicinal products for which reports of causing constipation symptoms may not have been recorded. Treatment of patients with intestinal obstruction/volvulus should be conducted under close supervision and with immediate medical assistance.

Venous thromboembolism

Cases of venous thromboembolism have been reported during antipsychotic medicinal product use. Since patients treated with antipsychotics often have acquired risk factors for VTE, all possible risk factors for venous thromboembolism should be identified before and during quetiapine treatment, and preventive measures should be taken.

Effect on the liver

Treatment with Seroquel XR should be discontinued if jaundice develops.

Pancreatitis

Cases of pancreatitis have been observed during clinical trials and post-marketing use. In post-marketing reports, although not all cases were complicated by the presence of risk factors, many patients had factors known to be associated with pancreatitis, such as elevated triglyceride levels, gallstones, and alcohol consumption.

Cardiovascular diseases

Seroquel XR 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 prolonged titration may be necessary in such cases.

Additional information

Data on the use of quetiapine in combination with divalproex or lithium in moderate to severe acute 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.

Lactose

Seroquel XR tablets contain lactose. Patients with rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Seroquel XR 50 mg contains 119 mg of lactose (anhydrous) per tablet.

Seroquel XR 150 mg contains 71 mg of lactose (anhydrous) per tablet.

Seroquel XR 200 mg contains 50 mg of lactose (anhydrous) per tablet.

Seroquel XR 300 mg contains 47 mg of lactose (anhydrous) per tablet.

Seroquel XR 400 mg contains 15 mg of lactose (anhydrous) per tablet.

Sodium

Seroquel XR 50 mg, 150 mg, and 200 mg prolonged-release tablets contain less than 1 mmol of sodium (23 mg per tablet) and can therefore be considered practically sodium-free.

Seroquel XR 300 mg prolonged-release tablets and Seroquel XR 400 mg prolonged-release tablets contain 27 mg of sodium per tablet, equivalent to 1.35% of the WHO recommended daily dose of 2 g sodium for adults.

Seroquel XR 300 mg contains 27 mg of sodium per tablet.

Seroquel XR 400 mg contains 27 mg of sodium per tablet.

Inappropriate use and abuse

Cases of inappropriate use and abuse of the medicinal product have been documented. Quetiapine should be prescribed cautiously to patients with a history of alcohol or substance abuse.

Use during pregnancy or breastfeeding.

The safety and efficacy of quetiapine use for treating pregnant women have not been established. Currently, there is no evidence of negative effects from animal studies. Potential effects on fetal vision organs have not been studied. Based on information from several pregnancies during which quetiapine was used, neonatal abstinence symptoms have been reported in newborns. Therefore, Seroquel XR may be prescribed during pregnancy only if the expected benefit justifies the potential risk. Neonates whose mothers took quetiapine during pregnancy have shown symptoms of drug withdrawal.

Published reports indicate that quetiapine passes into human breast milk, although the extent of drug penetration into milk is unknown. Breastfeeding women are advised to discontinue breastfeeding during quetiapine treatment.

Neonates whose mothers took antipsychotic medicinal products (including quetiapine) during the third trimester are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration after delivery. The following adverse reactions have been observed: agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory disorders, or feeding disorders. Therefore, neonates should be closely monitored.

Ability to affect reaction speed when driving vehicles or operating machinery.

Since the medicinal product primarily acts on the central nervous system, quetiapine may adversely affect activities requiring attention. Therefore, patients should be advised to avoid driving vehicles or operating machinery until their individual sensitivity to this effect is determined.

Method of Administration and Dosage.

Different dosing regimens exist for each indication. It is essential to ensure that the patient is prescribed a dosage appropriate to their condition.

Seroquel XR should be administered once daily, on an empty stomach. Tablets should be swallowed whole, without splitting, chewing, or crushing.

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

Seroquel XR 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 daily. The dose should be adjusted within the effective dose range of 400 mg to 800 mg daily, depending on clinical response and tolerability. For maintenance therapy in schizophrenia, dosage adjustment is not required.

Treatment of depressive episodes in bipolar disorder

Seroquel XR should be administered 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 treating bipolar disorder. Clinical studies indicate that for some patients experiencing tolerability issues, dose reduction to the minimum of 200 mg should be considered.

Prevention of relapse in bipolar disorder

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

Adjunctive treatment of major depressive episodes in MDD

Seroquel XR 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 and 300 mg/day, and at a dose of 50 mg/day in a short-term monotherapy study. The risk of adverse reactions increases with higher doses of the medicinal product. Therefore, the physician should ensure that the lowest effective dose is used for treatment, starting at 50 mg/day. The need to increase the dose from 150 to 300 mg/day should be based on assessment of the individual patient's condition.

Switching from Seroquel immediate-release tablets

For easier dose titration, patients currently receiving separate doses of Seroquel (immediate-release tablets) may be switched to Seroquel XR at an equivalent total daily dose administered once daily. Individual dose adjustments may be necessary.

Elderly patients

As with other antipsychotics and antidepressants, Seroquel XR should be used with caution in elderly patients, particularly during initial dose titration. Slower dose titration of Seroquel XR may be required, and the daily therapeutic dose may be lower than that used in younger patients. Mean plasma clearance of quetiapine was 30–50% lower in elderly patients compared to younger patients. Treatment in elderly patients should be initiated at 50 mg/day. The dose may be increased by 50 mg/day to an effective dose based on the individual patient's clinical response and tolerability.

In elderly patients with major depressive episodes in MDD, treatment should be initiated at a dose of 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 dose increase to 300 mg/day is required based on assessment of the individual patient, this should not occur earlier than Day 22.

The safety and efficacy of Seroquel XR in patients over 65 years of age with depressive episodes in bipolar disorder have not been studied.

Children

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

Patients with renal impairment

No dosage adjustment is necessary for patients with renal impairment.

Patients with hepatic impairment

Quetiapine is extensively metabolized by the liver. Therefore, Seroquel XR should be used with caution in patients with known hepatic impairment, particularly during initial dose titration. Treatment in patients with hepatic impairment should be initiated at 50 mg/day. The dose may be increased by 50 mg/day to an effective dose depending on the individual patient's clinical response and tolerability.

Overdose.

Symptoms

In general, reported signs and symptoms were consequences of the enhanced 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, disorientation, delirium and/or agitation, coma, and death. Patients with pre-existing severe cardiovascular disease may be at increased risk of overdose effects (see section "Special Warnings and Precautions for Use").

Management of overdose

During clinical trials, survival has been reported following acute overdose of up to 30 g of quetiapine. Most patients with overdose did not report adverse events or fully recovered from 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 leading to fatal outcome or coma, or QT prolongation were very rare after ingestion of 6 g of quetiapine as monotherapy. Additionally, the following events have been reported under conditions of 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 are at increased risk of overdose effects (see section "Special Warnings and Precautions for Use").

In general, reported signs and symptoms were consequences of enhanced known pharmacological effects of the medicinal product, such as somnolence and sedation, tachycardia, and hypotension.

There is no specific antidote for quetiapine. In cases of severe overdose symptoms, appropriate measures and intensive therapy should be considered, including restoration and maintenance of airway patency, adequate oxygenation and ventilation, and monitoring and support of cardiovascular function.

Based on published literature, patients with delirium and agitation, and clear signs of anticholinergic syndrome, may be treated with physostigmine at a dose of 1–2 mg (under continuous ECG monitoring). This is not a recommendation for standard treatment due to the potential negative effect of physostigmine on cardiac conduction. Physostigmine may be used in the absence of ECG abnormalities. 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 should be applied, such as intravenous fluid administration and/or sympathomimetics (adrenaline and dopamine should be avoided, as stimulation of beta-adrenergic receptors may worsen hypotension under conditions of alpha-adrenergic receptor blockade induced by quetiapine).

Since prevention of absorption has not been studied in quetiapine overdose, the need for gastric lavage should be considered, preferably within 1 hour after drug intake (after intubation if the patient is unconscious), along with administration of activated charcoal together with a laxative.

In cases of overdose with prolonged-release quetiapine, formation of gastric bezoars has been reported, and appropriate diagnostic imaging is recommended to determine further management strategy. Routine gastric lavage may be ineffective in removing gastric bezoars due to the sticky, gum-like consistency of the mass.

In some cases, endoscopic removal of the pharmacobezoar has been successfully performed.

Careful medical supervision and monitoring should continue until full recovery of the patient.

Adverse Reactions

The most commonly reported adverse drug reactions (ADRs) with quetiapine (≥ 10%) include somnolence, dizziness, headache, dry mouth, withdrawal symptoms (upon discontinuation), increased serum triglyceride levels, increased total cholesterol levels (predominantly LDL-cholesterol), decreased HDL-cholesterol levels, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.

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

ADRs associated with quetiapine treatment are listed below in Table 1.

Table 1. ADRs associated with quetiapine therapy.

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

Body systems	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Blood and lymphatic system disorders	Decreased hemoglobin levels²²	Leukopenia^1,28, decreased neutrophil count, increased eosinophil count²⁷	Neutropenia¹ Thrombocytopenia, anemia, decreased platelet count¹³	Agranulocytosis²⁶
Immune system disorders			Hypersensitivity (including skin allergic reactions)		Anaphylactic reaction⁵
Endocrine disorders		Hyperprolactinemia¹⁵, decreased total T4²⁴, decreased free T4²⁴, decreased total T3²⁴, increased TSH²⁴	Decreased free T3²⁴, hypothyroidism²¹		Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders	Increased serum triglyceride levels^10,30 Increased total cholesterol levels (especially LDL cholesterol)^11,30 Decreased HDL cholesterol^17,30 Increased body weight^8,30	Increased appetite, increased blood glucose levels up to hyperglycemia^6,30	Hyponatremia¹⁹ Diabetes mellitus^1,5 Worsening of pre-existing diabetes mellitus	Metabolic syndrome²⁹
Psychiatric disorders		Unusual dreams and nightmares, suicidal thoughts and suicidal behavior²⁰		Sleepwalking and related phenomena such as talking during sleep and sleep-related eating disorders
Nervous system disorders	Dizziness^4,16, somnolence^2,16, headache, extrapyramidal symptoms^1,21	Dysarthria	Seizures¹, restless legs syndrome, tardive dyskinesia^1,5, loss of consciousness^4,16 confusional state
Cardiac disorders		Tachycardia⁴, palpitations²³	QT interval prolongation^1,12,18, bradycardia³²			Cardiomyopathy and myocarditis
Eye disorders		Blurred vision
Vascular disorders		Orthostatic hypotension^4,16		Venous thromboembolism¹		Stroke³³
Respiratory, thoracic and mediastinal disorders		Dyspnea²³	Rhinitis
Gastrointestinal disorders	Dry mouth	Constipation, dyspepsia, vomiting²⁵	Dysphagia⁷	Pancreatitis¹, intestinal obstruction/ volvulus
Hepatobiliary disorders		Increased alanine aminotransferase (ALT) levels in serum³, increased gamma-GT levels³	Increased aspartate aminotransferase (AST) levels³ in serum	Jaundice⁵, hepatitis
Skin and subcutaneous tissue disorders					Angioedema⁵, Stevens-Johnson syndrome⁵	Toxic epidermal necrolysis, multiformal erythema, acute generalized exanthematous pustulosis, skin reactions with eosinophilia and systemic symptoms (DRESS), cutaneous vasculitis (DRESS), cutaneous vasculitis
Musculoskeletal and connective tissue disorders				Rhabdomyolysis
Renal and urinary disorders			Urinary retention
Pregnancy, puerperium and perinatal conditions						Neonatal withdrawal syndrome³¹
Reproductive system and breast disorders			Sexual dysfunction	Priapism, galactorrhea, breast enlargement, menstrual cycle disturbances
General disorders and administration site conditions	Withdrawal symptoms (upon discontinuation)^1,9	Mild asthenia, peripheral edema, irritability, fever		Malignant neuroleptic syndrome¹, hypothermia
Investigations				Increased blood creatine phosphokinase levels¹⁴

(1) See section "Special precautions".

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

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

(4) Like other antipsychotic medicinal products that block alpha1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension associated with dizziness, tachycardia, and, in some patients, syncope, particularly during the initial dose titration period (see section "Special precautions").

(5) The frequency of these ADRs was calculated based only on post-marketing data from the use of quetiapine in the immediate-release dosage form.

(6) Fasting blood glucose level ≥126 mg/dl (≥7.0 mmol/l) or postprandial blood glucose level ≥200 mg/dl (≥11.1 mmol/l) on at least one occasion.

(7) An 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, diarrhoea, vomiting, dizziness, and irritability. The frequency of these reactions markedly decreased within 1 week after discontinuation of treatment.

(10) Triglyceride level ≥200 mg/dl (≥2.258 mmol/l) (patients aged ≥18 years) or ≥150 mg/dl (≥1.694 mmol/l) (patients aged <18 years) on at least one occasion.

(11) Cholesterol level ≥240 mg/dl (≥6.2064 mmol/l) (patients aged ≥18 years) or ≥200 mg/dl (≥5.172 mmol/l) (patients aged <18 years) on at least one occasion. An increase in LDL-cholesterol level of ≥30 mg/dl (≥0.769 mmol/l) was observed very commonly. The mean value in patients with such an increase was 41.7 mg/dl (≥1.07 mmol/l).

(12) See text below.

(13) Platelet count ≤100 × 10⁹/l on at least one occasion.

(14) According to adverse event reports from clinical trials, elevated blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.

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

(16) May lead to falls.

(17) HDL-cholesterol level: <40 mg/dl (1.025 mmol/l) in males; <50 mg/dl (1.282 mmol/l) in females at any time.

(18) Number of patients with change in QTc interval duration from <450 ms to ≥450 ms with an increase of ≥30 ms. In placebo-controlled trials of quetiapine, 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 behaviour have been reported during therapy with quetiapine or in the early period following discontinuation of treatment.

(21) See section "Pharmacodynamics".

(22) Decrease in haemoglobin level to ≤13 g/dl (8.07 mmol/l) in males, ≤12 g/dl (7.45 mmol/l) in females occurred in 11% of patients treated with quetiapine across all studies, including open-label extension studies. The mean maximum decrease in haemoglobin at any time for 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 initiation of all studies. Deviations for total T4, free T4, total T3, and free T3 were <0.8 × ULN (pmol/l), and deviations for TSH were >5 mU/l at any time.

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

(26) Based on deviations in neutrophil count from ≥1.5 × 10⁹/l initially to <0.5 × 10⁹/l at any time during treatment, and on the presence of patients with severe neutropenia (<0.5 × 10⁹/l) and infection across all clinical trials of quetiapine.

(27) Based on deviations from normal baseline levels to potentially clinically significant values at any time after initiation of all studies. Deviations in eosinophil count were >1 × 10⁹ cells/l at any time.

(28) Based on deviations from normal baseline levels to potentially clinically significant values at any time after initiation of all studies. Deviations in leukocyte count were ≤3 × 10⁹ cells/l at any time.

(29) Based on adverse event reports of metabolic syndrome across all clinical trials of quetiapine.

(30) During clinical trials, some patients experienced worsening of more than one of the metabolic factors of body weight, blood glucose, and blood lipids.

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

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

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

Cases of QT interval prolongation, ventricular arrhythmias, sudden unexpected death, cardiac arrest, and torsades de pointes have been reported with the use of neuroleptics, considered to be a class-specific effect.

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 in association with quetiapine treatment.

Paediatric patients

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

Table 2.

ADRs in children and adolescents associated with quetiapine treatment that occur more frequently than in adults or are not observed in adult patients

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

Organ systems	Very common	Common
Endocrine system	Increased prolactin level1
Metabolism and nutrition disorders	Increased appetite
Nervous system disorders	Extrapyramidal symptoms3,4	Loss of consciousness
Vascular disorders	Increased blood pressure2
Respiratory, thoracic and mediastinal disorders		Rhinitis
Gastrointestinal disorders	Vomiting
General disorders and administration site conditions		Agitation3

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

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

4 See section "Pharmacodynamics".

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows continuous 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 through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister. 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca UK Limited.

Manufacturer's location and address of the place of business.

Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.