Kvetiksol xr
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Kvetixol XR (Quetixol XR)
Composition:
Active substance: quetiapine fumarate;
One prolonged-release film-coated tablet contains quetiapine fumarate equivalent to quetiapine 50 mg, 150 mg, 200 mg, 300 mg, or 400 mg;
Excipients: hypromellose, microcrystalline cellulose, anhydrous sodium citrate, magnesium stearate, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80;
for 50 mg and 300 mg tablets – iron oxide yellow (E 172), iron oxide red (E 172), iron oxide black (E 172);
for 200 mg tablets – iron oxide yellow (E 172), iron oxide red (E 172).
Pharmaceutical form. Prolonged-release film-coated tablets.
Main physicochemical properties:
50 mg: brown oval-shaped, biconvex, film-coated tablets, with "Q50" embossed on one side;
150 mg: white oval-shaped, biconvex, film-coated tablets, with "Q150" embossed on one side;
200 mg: yellow oval-shaped, biconvex, film-coated tablets, with "Q200" embossed on one side;
300 mg: light yellow oval-shaped, biconvex, film-coated tablets, with "Q300" embossed on one side;
400 mg: white oval-shaped, biconvex, film-coated tablets, with "Q400" embossed on one side.
Pharmacotherapeutic group. Antipsychotics. ATC code N05A H04.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action.
Quetiapine is an atypical antipsychotic agent. Quetiapine and its active metabolite norquetiapine interact with various types of neurotransmitter receptors. Quetiapine and norquetiapine have high selectivity for serotonin (5-HT2) receptors and dopamine D1 and D2 receptors in the brain. This combination of receptor antagonism with greater selectivity for 5-HT2 receptors relative to D2 receptors is considered responsible for the clinical antipsychotic effects of quetiapine and its low propensity for extrapyramidal side effects compared to typical antipsychotics. Quetiapine and norquetiapine also have high affinity for histaminergic and α1-adrenergic receptors, but lower affinity for α2-adrenergic receptors and serotonin 5-HT1A receptors. Quetiapine has no affinity for muscarinic cholinergic receptors or benzodiazepine receptors, whereas norquetiapine has moderate to high affinity for several subtypes of muscarinic receptors, which may explain anticholinergic (muscarinic) effects.
Inhibition of the norepinephrine transporter (NET) by norquetiapine, as well as partial agonist activity at 5HT1A receptors, may contribute to the therapeutic efficacy of the drug Quetiksol XR as an antidepressant.
Pharmacodynamic effects.
Quetiapine is known to be active in tests of antipsychotic activity such as conditioned avoidance. Quetiapine blocks dopamine agonist effects, as confirmed by behavioral response assessments or electrophysiological studies, and increases concentrations of dopamine metabolites, reflecting neurochemical expression of D2 receptor blockade.
Preclinical studies evaluating the potential for development of extrapyramidal symptoms have shown that quetiapine has an atypical activity profile and differs from standard antipsychotic agents. With prolonged administration, quetiapine does not lead to excessive sensitivity of dopaminergic D2 receptors. At doses effective for blocking dopaminergic D2 receptors, quetiapine causes only mild catalepsy.
Following prolonged administration, quetiapine has demonstrated selectivity for the limbic system, evidenced by its ability to block depolarization in A10 mesolimbic neurons but not in A9 nigrostriatal neurons, where dopamine is located.
Clinical safety
It is known that treatment with quetiapine may cause dose-dependent reduction in thyroid hormone levels.
Available data from placebo-controlled studies in elderly patients with psychosis associated with dementia show that the incidence of cardiovascular adverse events per 100 patient-years in the quetiapine group was no higher than in patients receiving placebo.
Cataract
Clinical data from a study evaluating the cataractogenic potential of quetiapine (200–800 mg/day) compared to risperidone (2–8 mg/day) in patients with schizophrenia or schizoaffective disorder showed that the percentage of patients with increased lens opacification was no higher in the quetiapine group (4%) compared to those receiving risperidone (10%) after at least 21 months of treatment.
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 Quetiksol XR. Steady-state peak molar concentrations of the active metabolite norquetiapine are about 35% of those observed for 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 Quetiksol XR administered once daily versus immediate-release Quetiksol (quetiapine fumarate immediate release) administered twice daily, the area under the concentration-time curve (AUC) is equivalent, but the maximum plasma concentration (Cmax) is approximately 13% lower at steady state. When comparing Quetiksol XR with immediate-release Quetiksol, the AUC of the metabolite norquetiapine is 18% lower.
In a study evaluating the effect of food on the bioavailability of quetiapine, it was found that high-fat meals caused statistically significant increases in Cmax and AUC of Quetiksol XR by approximately 50% and 20%, respectively. It cannot be excluded that the effect of high-fat food on this dosage form may be greater. Light meals do not have a significant effect on Cmax and AUC of quetiapine. Quetiksol 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-life (t1/2) of quetiapine and norquetiapine is 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 active metabolite norquetiapine is excreted in urine.
Special populations
Gender
The pharmacokinetics of quetiapine in women and men do not differ.
Elderly patients
The average clearance of quetiapine in elderly patients is 30–50% lower than in patients aged 18–65 years.
Patients with renal impairment
In patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), the average plasma clearance of quetiapine is reduced by approximately 25%, but individual clearance values remain within the range typical for healthy individuals.
Patients with hepatic impairment
In patients with liver disease (compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since extensive hepatic metabolism of quetiapine occurs, plasma concentrations of quetiapine may increase in patients with hepatic impairment; therefore, dose adjustment may be required for this patient group (see section "Dosage and administration").
Clinical characteristics.
Indications.
Quetixol XR is indicated for the treatment of:
- schizophrenia, including prevention of relapse in patients with stable schizophrenia who have been maintained on Quetixol XR therapy;
- bipolar disorder, specifically:
- treatment of moderate to severe manic episodes in bipolar disorder;
- treatment of major depressive episodes in bipolar disorder;
- prevention of disease relapse in patients with bipolar disorder who have manic or depressive episodes responsive to quetiapine;
- as adjunctive therapy in major depressive episodes in patients with major depressive disorder (MDD) who have had a suboptimal response to antidepressant monotherapy; prior to initiating therapy, the prescriber should carefully consider the safety profile of Quetixol XR (see section "Special precautions").
Contraindications.
- Hypersensitivity to any component of the drug.
- Concomitant use of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone (see section "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Since quetiapine acts primarily on the central nervous system (CNS), it should be used with caution in combination with other agents having similar effects and with alcohol.
Quetiapine should be used with caution when administered concomitantly with serotonergic medicinal products such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as this may increase the risk of developing serotonin syndrome, a potentially life-threatening condition (see section "Special precautions").
The drug should be prescribed with caution in patients receiving other agents with anticholinergic (muscarinic) effects (see section "Special precautions").
CYP 3A4 is the key enzyme involved in the cytochrome P450-mediated metabolism of quetiapine. In a study of interaction in healthy volunteers, concomitant administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) resulted in a 5- to 8-fold increase in quetiapine AUC. Therefore, concomitant use of quetiapine with CYP 3A4 inhibitors is contraindicated. Grapefruit juice should also not be consumed during quetiapine therapy.
In a multiple-dose 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 exposure observed with quetiapine alone, although a greater effect was observed in some patients. Due to this interaction, plasma concentrations may be reduced; therefore, dose adjustment of Quetixol XR should be considered for each patient based on clinical response. Concomitant administration of quetiapine with phenytoin (another microsomal enzyme inducer) leads to a 450% increase in quetiapine clearance. Initiation of quetiapine therapy in patients taking a hepatic enzyme inducer should only be considered if the physician judges that the benefits of quetiapine outweigh the risks associated with discontinuation of the enzyme inducer. It is important that any changes in the use of the inducer be made gradually. The dose of quetiapine may need to be reduced when phenytoin, carbamazepine, or other hepatic enzyme inducers are discontinued or replaced with a drug that does not induce hepatic microsomal enzymes (e.g., sodium valproate) (see section "Special precautions").
The pharmacokinetics of quetiapine were only slightly altered after concomitant administration with the antidepressants imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor).
The pharmacokinetics of quetiapine were not significantly altered by concomitant administration with risperidone or haloperidol. Concomitant use of quetiapine and thioridazine increases quetiapine clearance by approximately 70%.
The pharmacokinetics of quetiapine were not altered after concomitant administration with cimetidine.
The pharmacokinetics of lithium were not altered by concomitant administration with quetiapine. Data from a 6-week randomized study comparing lithium plus quetiapine versus placebo plus quetiapine in adult patients with acute mania showed an increased incidence of extrapyramidal symptoms (particularly tremor), somnolence, and weight gain in the group receiving lithium compared to the placebo group.
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 these agents, an increased incidence of leukopenia and neutropenia was observed in the group receiving both drugs compared to groups receiving either drug alone.
Studies on interaction with cardiovascular drugs have not been conducted.
Caution should be exercised when quetiapine is used concomitantly with medicinal products that alter electrolyte balance or prolong the QT interval.
In patients taking 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 Kvetiksol XR is indicated for the treatment of several conditions, the safety profile of the drug should be carefully considered with regard to the specific diagnosis established for the patient and the dose being administered.
Long-term efficacy and safety of concomitant 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.
Children
Quetiapine is not recommended for use in children and adolescents under 18 years of age due to lack of data on its use in this age group. Clinical trials of quetiapine have shown that, in addition to the known safety profile established for adults (see section "Adverse reactions"), the frequency of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, vomiting, rhinitis, syncope), or may have different complications in children and adolescents (extrapyramidal symptoms and irritability), as well as increased blood pressure, which had not been previously observed in studies involving adult patients. In addition, changes in thyroid function parameters were observed in children and adolescents.
It should also be noted that the delayed impact of quetiapine treatment on growth and sexual maturation has not been studied for periods exceeding 26 weeks. The long-term impact on cognitive and behavioral development is unknown.
It is known that during placebo-controlled clinical trials of quetiapine involving pediatric patients, treatment with quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania, and depression (see section "Adverse reactions").
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission is achieved. Since improvement may not occur during the first weeks of treatment or longer, patients should be closely monitored until such improvement occurs. According to general clinical experience, the risk of suicide may increase in the early stages of recovery.
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 quetiapine is prescribed may also be associated with an increased risk of suicide-related events. Additionally, these disorders may coexist with depressive episodes. Therefore, the same precautions should be taken when treating other psychiatric disorders as are taken when treating depressive episodes.
Patients with a history of suicide-related events or those demonstrating a significant degree of suicidal thoughts prior to treatment initiation have a higher risk of suicidal thoughts or suicide attempts and require close monitoring during treatment. It is known that a meta-analysis of placebo-controlled clinical trials involving antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressant treatment compared to placebo in patients under 25 years of age.
Close supervision of patients, particularly those at high risk, should 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 occur.
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 young patients (under 25 years of age) treated with quetiapine compared to those treated with placebo (3.0% vs. 0%, respectively).
In clinical trials involving patients with MDD, the frequency of suicide-related events in young patients (under 25 years of age) was 2.1% (3/144) in the group receiving quetiapine and 1.3% (1/75) in the placebo group. A population-based retrospective analysis of quetiapine use in treating patients with MDD revealed an increased risk of self-harm and suicide in patients aged 24 to 64 years without a history of self-harm when quetiapine was used with other antidepressants.
Metabolic risk
Due to changes observed during clinical trials regarding body weight, blood glucose (see hyperglycemia), and lipid parameters, there is a potential risk of worsening metabolic profile in individual patients, which may require appropriate treatment (see section "Adverse reactions").
Orthostatic hypotension
Treatment with quetiapine has been associated with orthostatic hypotension and accompanying dizziness (see section "Adverse reactions"), which, similar to somnolence, usually occur during the dose titration period. These phenomena may lead 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.
Kvetiksol should be used with caution in patients with established cardiovascular and cerebrovascular diseases or other conditions that may lead to hypotension.
Quetiapine may cause orthostatic hypotension, particularly during the initial period of gradual dose escalation. If this occurs, the dose or rate of dose escalation should be reduced. A slower titration regimen may be considered for patients with cardiovascular diseases.
Seizures
There was no difference in seizure frequency between patients taking quetiapine and those taking placebo. There are no data on seizure frequency in patients with a history of seizure disorders. As with other antipsychotic drugs, caution is recommended when prescribing the drug to patients with a history of seizures (see section "Adverse reactions").
EPS
It is known that in placebo-controlled trials, quetiapine was associated with an increased frequency of EPS compared to placebo in adult patients receiving treatment for major depressive episodes associated with bipolar disorder (see section "Adverse reactions").
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 these symptoms may be harmful.
Tardive dyskinesia
If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing the drug.
Symptoms of tardive dyskinesia may worsen and occur even after discontinuation of therapy (see section "Adverse reactions").
Somnolence and dizziness
Treatment with quetiapine is associated with somnolence and similar symptoms such as sedation (see section "Adverse reactions"). In clinical trials, it was reported that during treatment of patients with bipolar depression, such symptoms usually occurred within the first 3 days of treatment and were predominantly mild to moderate in intensity. For patients with bipolar depression who experience somnolence, monitoring may be necessary for 2 weeks after the onset of somnolence or until symptoms resolve, or consideration may need to be given to discontinuing treatment.
Sleep apnea syndrome
Sleep apnea syndrome has been reported in patients taking quetiapine; therefore, quetiapine should be used with caution in patients with a history of sleep apnea syndrome or those at risk of developing it (e.g., patients with excess body weight/obesity, male patients, patients receiving concomitant therapy with CNS depressant drugs).
Malignant neuroleptic syndrome
Malignant neuroleptic syndrome may be associated with treatment with antipsychotic drugs, including quetiapine (see section "Adverse reactions"). Clinical manifestations include hyperthermia, altered mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, the drug should be discontinued and appropriate treatment initiated.
Serotonin syndrome
Concomitant use of the medicinal product Kvetiksol 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 forms of interaction").
If concomitant treatment with other serotonergic medicinal products is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and during dose increases. Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy depending on the severity of symptoms.
Severe neutropenia and agranulocytosis
It is known that severe neutropenia (neutrophil count < 0.5 × 10⁹/L) occurred during quetiapine trials. Most cases of severe neutropenia occurred within several months after starting quetiapine therapy. There is no apparent dose-dependency. Post-marketing reports have included cases of severe neutropenia with fatal outcomes. Possible risk factors for neutropenia include prior low white blood cell count and a history of drug-induced neutropenia. Cases of agranulocytosis have occurred in patients without pre-existing risk factors. The use of quetiapine should be discontinued in patients with neutrophil counts < 1.0 × 10⁹/L. Patients should be monitored for signs of infection and neutrophil counts should be followed (until they exceed 1.5 × 10⁹/L).
The possibility of developing neutropenia should be considered in patients with infection, especially in the absence of obvious influencing factors, as well as in patients with unexplained fever, and appropriate clinical measures should be taken.
Patients should be advised to immediately report symptoms characteristic of agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during quetiapine treatment, and timely monitoring of white blood cell count and absolute neutrophil count should be performed, especially in the absence of triggering factors.
Anticholinergic (muscarinic) effects
Norquetiapine, an active metabolite of quetiapine, has moderate to high affinity for several subtypes of muscarinic receptors. This leads to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used at recommended doses, when quetiapine is used concomitantly with other drugs having anticholinergic effects, and in cases of overdose. Quetiapine should be used with caution in patients receiving drugs exhibiting anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with urinary retention, significant prostatic hyperplasia, intestinal obstruction, increased intraocular pressure, or closed-angle glaucoma present at the time of treatment or in medical history (see sections "Pharmacological properties", "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Adverse reactions").
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").
Interactions
See also section "Interaction with other medicinal products and other forms of interaction".
Concomitant use of quetiapine with strong hepatic enzyme inducers such as carbamazepine or phenytoin significantly reduces quetiapine plasma concentrations, which may reduce its efficacy. Treatment with quetiapine in patients receiving a hepatic enzyme inducer may only be initiated if the physician considers the benefit of using the drug to outweigh the risks of discontinuing the enzyme inducer. It is important that any changes in the use of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate).
Effect on body weight
Weight gain has been reported during quetiapine treatment, which should be monitored and managed appropriately according to recommendations for antipsychotic use (see section "Adverse reactions").
Hyperglycemia
In rare cases, hyperglycemia and/or development or exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, including several cases with fatal outcomes, have been reported (see section "Adverse reactions"). In some cases, these events occurred in patients with increased body weight, which could be an influencing factor. Adequate clinical monitoring according to appropriate recommendations for antipsychotic use is recommended. Patients receiving treatment with any antipsychotic agent, including quetiapine, should be monitored for possible signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes or risk factors for developing diabetes should be regularly monitored for possible worsening of glucose control. Body weight should be monitored regularly.
Lipids
Cases of increased triglycerides, low-density lipoproteins (LDL), and total cholesterol, as well as decreased high-density lipoproteins (HDL), have been described (see section "Adverse reactions"). Treatment according to clinical indications is required when lipid levels change.
QT interval prolongation
During clinical trials and according to instructions for use, no consistent increase in the absolute QT interval duration was observed with quetiapine. In the post-marketing period, QT interval prolongation has been reported with therapeutic doses of the drug (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. When prescribing quetiapine concomitantly with drugs that prolong the QT interval or other neuroleptics, caution is required (see section "Interaction with other medicinal products and other forms of interaction"), especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure (CHF), cardiac hypertrophy, hypokalemia, or hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").
Cardiomyopathy and myocarditis
Cases of cardiomyopathy and myocarditis have been reported during quetiapine use in clinical trials and in the post-marketing period (see section "Adverse reactions"). In patients suspected of having cardiomyopathy or myocarditis, consideration should be given to discontinuing quetiapine treatment.
Severe skin reactions
Very rare cases of severe skin adverse reactions (SCAR) associated with quetiapine treatment have been reported, 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 as a combination of symptoms: widespread 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 observed within 6 weeks after starting quetiapine therapy. If signs and symptoms indicating such severe skin reactions appear, quetiapine should be immediately discontinued and alternative treatment considered.
Elderly patients with psychosis associated with dementia
Quetiapine is not approved for the treatment of psychosis associated with dementia.
In patients with dementia, an almost threefold increased risk of adverse cerebrovascular events has been observed with the use of some atypical antipsychotics. The mechanism of this increased risk is unknown. The increased risk cannot be excluded for other antipsychotics or for other patient categories. Quetiapine should be used with caution in patients with risk factors for stroke.
According to a meta-analysis of atypical antipsychotics, elderly patients suffering from psychosis associated with dementia represent a group at increased risk of fatal outcome compared to placebo. However, data from two 10-week placebo-controlled studies using quetiapine in similar populations (mean age 83 years, range 56–99 years) showed a mortality rate of 5.5% in patients treated with quetiapine compared to 3.2% in the placebo group. Deaths during the studies were due to various causes, which are expected for this patient population.
Elderly patients with Parkinson's disease/parkinsonism
A retrospective population-level study examining the use of quetiapine for treating patients with MDD showed an increased risk of fatal outcome in patients aged 65 years and older during quetiapine use. This association was not observed when patients with Parkinson's disease were excluded from the study. Caution should be exercised when prescribing quetiapine to elderly patients with Parkinson's disease.
Dysphagia
Dysphagia has been reported with the use of quetiapine (see section "Adverse reactions"). Quetiapine should be used with caution in patients at risk of aspiration pneumonia.
Constipation and intestinal obstruction
Constipation is a risk factor for the development of intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with the use of quetiapine (see section "Adverse reactions"). These reports include reports of fatal cases in patients at higher risk of developing intestinal obstruction, including those receiving multiple drugs that reduce intestinal peristalsis and/or those who may not report symptoms of constipation. Patients with intestinal obstruction/ileus should be monitored carefully and provided with immediate medical assistance.
Hepatic effects
Quetiapine should be discontinued if jaundice occurs.
Venous thromboembolism (VTE)
Cases of VTE have been reported with the use of antipsychotic agents. Since patients taking antipsychotic agents often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during quetiapine treatment, and preventive measures should be taken.
Pancreatitis
Cases of pancreatitis have been reported in clinical trials and during the post-marketing period. Post-marketing reports indicated that many patients had factors known to be associated with pancreatitis, such as elevated triglyceride levels, gallstones, and alcohol consumption.
Additional information
Data on the use of quetiapine in combination with divalproex or lithium in moderate to severe manic episodes are limited, but combination therapy was well tolerated (see section "Adverse reactions"). These data showed an additive effect by week 3 of treatment.
Inappropriate use and abuse
Cases of inappropriate use and abuse of the drug have been reported. Quetiapine should be prescribed with caution to patients with a history of alcohol and drug abuse.
Use during pregnancy or breastfeeding.
Pregnancy
First trimester
There is only a limited amount of published data on the effect of quetiapine during pregnancy (i.e., approximately 300–1000 pregnancy outcomes), including individual case reports and some observational studies, which do not indicate an increased risk of developmental abnormalities due to quetiapine treatment. However, based on all available data, a definitive conclusion cannot be made. Animal studies have shown reproductive toxicity; therefore, quetiapine should be prescribed only when the expected benefit to the mother outweighs the potential risk to the fetus.
Third trimester
The use of antipsychotic drugs (including quetiapine) during the third trimester of pregnancy may lead to adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after birth. Reports have included agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders. Therefore, newborns should be closely monitored.
Period of breastfeeding
Based on very limited data from published reports on the excretion of quetiapine into human breast milk, it is known that quetiapine passes into breast milk, although the extent of this passage is unknown. Due to the lack of reliable data, a decision regarding discontinuation of breastfeeding or discontinuation of Kvetiksol XR therapy should be made, taking into account the benefit of treatment for the mother and the benefit of breastfeeding for the child.
Fertility
The effect of quetiapine on human fertility has not been evaluated. Effects related to elevated prolactin levels were observed in rats, although they are not directly relevant to humans.
Ability to affect reaction speed when driving vehicles or operating machinery.
Since the drug primarily acts on the CNS, quetiapine may negatively affect activities requiring increased attention. Therefore, patients should not drive vehicles or operate machinery until their individual sensitivity to this effect has been determined.
Dosage and Administration
Different dosing regimens exist for each indication. It is essential to ensure that the patient receives a dose appropriate to their condition. Kvetiksol XR should be administered once daily on an empty stomach. Tablets should be swallowed whole and must not be split, chewed, or crushed.
Adult Patients
Treatment of schizophrenia and moderate to severe manic episodes in bipolar disorder
Kvetiksol 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 400–800 mg daily, depending on clinical response and tolerability. No dose adjustment is required for maintenance therapy in schizophrenia.
Treatment of major depressive episodes in bipolar disorder
Kvetiksol XR 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 have not shown additional benefit with a 600 mg dose compared to 300 mg. However, a dose of 600 mg 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 patients experiencing intolerance, consideration should be given to reducing the dose to the minimum effective dose of 200 mg.
Prevention of relapse in bipolar disorder
To prevent subsequent manic, mixed, or depressive episodes in bipolar disorder, patients who have responded to Kvetiksol XR during acute treatment should continue therapy with Kvetiksol XR at the same bedtime dose. The dose of Kvetiksol XR 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 dose for maintenance therapy.
Adjunctive treatment of major depressive episodes in MDD
Kvetiksol 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 therapy trials (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine), antidepressant effects were observed with doses of 150 mg/day and 300 mg/day. A dose of 50 mg/day was used in a short-term monotherapy trial. The risk of adverse reactions increases with higher doses. Therefore, physicians should ensure that the lowest effective dose is used, starting at 50 mg/day. Any decision to increase the dose from 150 mg/day to 300 mg/day should be based on individual patient assessment.
Switching from Kvetiksol immediate-release tablets
Patients currently receiving Kvetiksol immediate-release tablets can be switched to Kvetiksol XR at an equivalent total daily dose administered once daily for easier dosing. A dose titration period may be necessary to maintain clinical response.
Elderly Patients
As with other antipsychotics and antidepressants, Kvetiksol XR should be used with caution in elderly patients, especially at the beginning of treatment and during dose titration. Slower dose titration may be required, and the daily therapeutic dose may be lower than that used in younger patients. The mean plasma clearance of quetiapine is reduced by 30–50% in elderly patients compared to younger patients. Treatment should be initiated at a dose of 50 mg/day. The dose may be gradually increased by 50 mg/day to achieve an effective dose, depending on the individual patient’s clinical response and tolerability.
For elderly patients with depressive episodes in MDD, treatment should begin at 50 mg/day for Days 1–3, increased to 100 mg/day on Day 4, and to 150 mg/day on Day 8. The lowest effective dose should be used, starting at 50 mg/day. If, based on individual patient assessment, an increase to 300 mg/day is required, this should not occur earlier than Day 22 of treatment.
The safety and efficacy of the medicinal product in patients aged 65 years and older with depressive episodes in bipolar disorder have not been studied.
Renal Impairment
No dose adjustment is necessary for patients with renal impairment.
Hepatic Impairment
Quetiapine is extensively metabolized in the liver. Therefore, Kvetiksol XR should be used with caution in patients with known hepatic impairment, particularly during the initial dose titration period. Treatment should be initiated at a dose of 50 mg/day. The dose may be increased in 50 mg/day increments to achieve an effective dose, depending on the individual patient’s clinical response and tolerability.
Children
Kvetiksol XR is not recommended for use in children due to lack of data supporting its use in this age group.
Overdose
Symptoms
Overall, symptoms and manifestations reported in overdose cases were consequences of the enhanced known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, arterial hypotension, and anticholinergic effects.
Overdose may lead to QT interval prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma, and fatal outcome. Patients with pre-existing severe cardiovascular disease may have an increased risk of overdose effects (see section "Special Warnings and Precautions for Use").
Treatment
There is no specific antidote for quetiapine. In cases of severe intoxication, appropriate supportive measures and intensive care procedures 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, agitation, and anticholinergic syndrome may be treated with physostigmine (1–2 mg) administered under continuous ECG monitoring. However, this treatment is not recommended as standard due to the potential adverse effects of physostigmine on cardiac conduction. Physostigmine may be used only if there are no ECG abnormalities. Physostigmine must not be used in cases of arrhythmias, any degree of heart block, or QRS complex widening.
In cases of severe overdose, gastric lavage may be considered (after intubation if the patient is unconscious), but not later than 1 hour after drug ingestion. Activated charcoal may also be administered.
Persistent arterial hypotension following quetiapine overdose should be managed using appropriate measures such as intravenous fluids and/or sympathomimetic agents.
Adrenaline and dopamine should be avoided, as beta-stimulation may worsen hypotension in the presence of alpha-blockade induced by quetiapine.
Close medical monitoring and observation should continue until the patient has fully recovered.
In cases of overdose with extended-release quetiapine, a prolonged sedative effect and delayed recovery are observed, in contrast to the effects of immediate-release quetiapine formulations.
Cases of overdose with extended-release quetiapine have reported possible formation of a gastric pharmacobezoar. In such patients, appropriate diagnostic imaging of gastric contents should be performed. Routine gastric lavage may be ineffective in removing gastric foreign bodies due to the sticky, gum-like consistency of the mass.
In some cases, successful endoscopic removal of the pharmacobezoar has been performed.
Adverse Reactions
The most commonly reported adverse reactions during quetiapine administration (≥10%) were: somnolence, dizziness, dry mouth, headache, withdrawal symptoms (upon discontinuation), increased serum triglycerides, increased total serum cholesterol (predominantly LDL cholesterol), decreased HDL cholesterol, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.
As with other antipsychotics, quetiapine use has been associated with weight gain, syncope, neuroleptic malignant syndrome, leukopenia, and peripheral edema.
Adverse reaction frequencies are defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).
Blood and lymphatic system disorders: very common – decreased hemoglobin levels22; common – leukopenia1,28, neutrophil count decrease, eosinophilia27; uncommon – neutropenia1, thrombocytopenia, anemia, decreased platelet count13; rare – agranulocytosis26.
Immune system disorders: uncommon – hypersensitivity (including skin allergic reactions); very rare – anaphylactic reaction5.
Endocrine disorders: common – hyperprolactinemia15, decreased total T424, decreased free T424, decreased total T324, increased TSH24; uncommon – decreased free T324, hypothyroidism21; very rare – syndrome of inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders: very common – increased serum triglycerides10,30, increased total cholesterol (particularly LDL cholesterol)11,30, decreased HDL cholesterol17,30, weight gain8,30; common – increased appetite, increased glucose levels reaching hyperglycemia thresholds6,30; uncommon – hyponatremia19, diabetes mellitus1,5, worsening of diabetes; rare – metabolic syndrome29.
Psychiatric disorders: common – abnormal dreams and nightmares, suicidal thoughts and behavior20; rare – sleepwalking and related events such as sleep talking and sleep-related eating disorders.
Nervous system disorders: very common – dizziness4,16, somnolence2,16, headache, extrapyramidal symptoms1,21; common – dysarthria; uncommon – seizures1, restless legs syndrome, tardive dyskinesia1,5, loss of consciousness4,16.
Cardiac disorders: common – tachycardia4, palpitations23; uncommon – QT interval prolongation1,12,18, bradycardia32; frequency not known – cardiomyopathy and myocarditis.
Vascular disorders: common – orthostatic hypotension4,16; rare – venous thromboembolism1; frequency not known – stroke33.
Eye disorders: common – blurred vision.
Respiratory, thoracic and mediastinal disorders: common – dyspnea23; uncommon – rhinitis.
Gastrointestinal disorders: very common – dry mouth; common – constipation, dyspepsia, vomiting25; uncommon – dysphagia7; rare – pancreatitis1, intestinal obstruction/ileus.
Hepatobiliary disorders: common – increased transaminase levels (alanine aminotransferase3 [ALT], gamma-glutamyl transferase3 [gamma-GT]) in serum; uncommon – increased aspartate aminotransferase3 [AST] levels in serum; rare – jaundice5, hepatitis.
Skin and subcutaneous tissue disorders: very rare – angioedema5, Stevens-Johnson syndrome5; frequency not known – toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS); cutaneous vasculitis.
Musculoskeletal and connective tissue disorders: very rare – rhabdomyolysis.
Renal and urinary disorders: uncommon – urinary retention.
Pregnancy, puerperium and perinatal conditions: frequency not known – withdrawal syndrome in newborns31.
Reproductive system and breast disorders: uncommon – sexual dysfunction; rare – priapism, galactorrhea, breast enlargement, menstrual cycle irregularities.
General disorders and administration site conditions: very common – withdrawal symptoms (upon discontinuation)1,9; common – mild asthenia, peripheral edema, irritability, fever; rare – neuroleptic malignant syndrome1, hypothermia.
Investigations: rare – increased blood creatine phosphokinase levels14.
Notes:
1 See section "Special precautions for use";
2 Somnolence is typically observed during the first two weeks of treatment and usually resolves with continued quetiapine therapy;
3 Asymptomatic increases (shift from normal to >3 ULN at any time) in transaminase (ALT, AST) or gamma-GT levels have been observed in some patients receiving quetiapine; such increases were generally reversible with continued quetiapine treatment;
4 Like other antipsychotics that block α1-adrenergic receptors, quetiapine may frequently cause orthostatic hypotension, accompanied by dizziness, tachycardia, and in some patients, syncope, particularly during initial dose titration (see section "Special precautions for use");
5 Frequency estimates for these adverse reactions are based solely on post-marketing data;
6 Blood glucose ≥126 mg/dL (≥7.0 mmol/L) fasting or ≥200 mg/dL (≥11.1 mmol/L) postprandial 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 from baseline, occurring predominantly during the first weeks of therapy in adults;
9 Withdrawal symptoms most commonly observed in short-term placebo-controlled monotherapy trials included insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability; the frequency of these reactions decreased significantly within one week after stopping treatment;
10 Triglyceride level ≥200 mg/dL (≥2.258 mmol/L) (patients ≥18 years) or ≥150 mg/dL (≥1.694 mmol/L) (patients <18 years), at least once;
11 Cholesterol level ≥240 mg/dL (≥6.2064 mmol/L) (patients ≥18 years) or ≥200 mg/dL (≥5.172 mmol/L) (patients <18 years), at least once;
Increase in LDL cholesterol ≥30 mg/dL (≥0.769 mmol/L) occurred very commonly; mean value among patients with such 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 adverse reaction reports from clinical trials, increased blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome;
15 Prolactin levels (patients >18 years): >20 µg/L (>869.56 pmol/L) in males; >30 µg/L (>1304.34 pmol/L) in females – at any time;
16 May lead to falls;
17 HDL cholesterol: <40 mg/dL (1.025 mmol/L) in males; <50 mg/dL (1.282 mmol/L) in females – at any time;
18 Number of patients with QTc interval change from <450 msec to ≥450 msec with increase ≥30 msec in placebo-controlled quetiapine trials; mean change and number of patients reaching clinically significant shift were similar in quetiapine and placebo groups;
19 Shift from >132 mmol/L to ≤132 mmol/L at least once;
20 Suicidal thoughts and behavior were reported during quetiapine therapy or immediately after discontinuation (see sections "Pharmacological properties" and "Special precautions for use");
21 See section "Pharmacological properties";
22 Hemoglobin decrease to ≤13 g/dL (8.07 mmol/L) in males, ≤12 g/dL (7.45 mmol/L) in females, observed at least once in 11% of quetiapine-treated patients across all studies including open-label trials; mean maximum decrease in hemoglobin at any time was 1.50 g/dL for these patients;
23 These events often occurred in the context of tachycardia, dizziness, orthostatic hypotension and/or pre-existing cardiac/respiratory disease;
24 Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies; deviations: total T4, free T4, total T3, and free T3 <0.8 × ULN (pmol/L), TSH >5 mIU/L at any time;
25 Based on increased frequency of vomiting in elderly patients (≥65 years);
26 Based on neutrophil count deviation from >1.5×109/L at baseline to <0.5×109/L at any time during treatment, and on patients with severe neutropenia (<0.5×109/L) and infection across all quetiapine clinical trials (see section "Special precautions for use");
27 Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies; eosinophil deviation >1×109 cells/L at any time;
28 Based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies; leukocyte deviation ≤3×109 cells/L at any time;
29 Based on adverse reaction reports of metabolic syndrome from all quetiapine clinical trials;
30 During clinical trials, some patients experienced worsening in more than one metabolic parameter: body weight, blood glucose, and lipid levels (see section "Special precautions for use");
31 See section "Use in pregnancy or lactation";
32 May occur during or shortly before initiation of therapy and may be associated with hypotension and/or syncope; frequency is based on adverse reaction reports of bradycardia and related events observed in all quetiapine clinical trials;
33 Based on data from one retrospective, non-randomized epidemiological study.
With the use of neuroleptics, cases of QT interval prolongation on ECG, ventricular arrhythmias, torsade de pointes arrhythmia, sudden unexplained death, and cardiac arrest have been reported; these effects are considered class-specific.
Serious skin adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with quetiapine treatment.
Children. The adverse reactions listed above observed in adults also occur in children. Below are adverse reactions with higher incidence in this age group or not observed in adults.
Adverse reaction frequencies are defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).
Endocrine disorders: very common – increased prolactin levels1.
Metabolism and nutrition disorders: very common – increased appetite.
Nervous system disorders: very common – extrapyramidal symptoms3,4; common – loss of consciousness.
Vascular disorders: very common – increased blood pressure2.
Respiratory, thoracic and mediastinal disorders: common – rhinitis.
Gastrointestinal disorders: very common – vomiting.
General disorders and administration site conditions: common – irritability3.
Notes:
1 Prolactin levels (patients <18 years): >20 µg/L (>869.56 pmol/L) in males; >26 µg/L (>1130.428 pmol/L) in females at any time; less than 1% of patients had prolactin levels >100 µg/L;
2 Based on deviations above clinically significant thresholds (adapted from National Institutes of Health criteria) or increases >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time, according to data from short-term (3–6 weeks) placebo-controlled trials in children and adolescents;
3 Frequency is similar to that observed in adults, but irritability may manifest differently in children and adolescents compared to adults;
4 See section "Pharmacological properties".
Reporting suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.
Shelf life. 3 years.
Storage conditions.
Store in the original packaging to protect from moisture. No special temperature storage requirements. Keep out of reach of children.
Packaging.
10 tablets per blister, 3 blisters per cardboard pack.
Prescription status. Prescription only.
Manufacturer.
Merckle GmbH
Manufacturer's address and location of operations.
Graf-Arco-Strasse 3, Donautal, Ulm, Baden-Wuerttemberg, 89079, Germany.