Kvetro 100
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KVEtiROn 25 (QuetiROn 25) KVEtiROn 100 (QuetiROn 100) KVEtiROn 200 (QuetiROn 200)
Composition:
Active substance: quetiapine;
1 tablet contains quetiapine fumarate, calculated as 100 % dry substance: quetiapine 25 mg, 100 mg or 200 mg;
Excipients: lactose monohydrate, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, povidone, magnesium stearate; coating: Opadry II White (KvetiRon 25, KvetiRon 200) (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171)), Opadry II Yellow (KvetiRon 100) (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171), quinoline yellow (E 104), iron oxide red (E 172), iron oxide yellow (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
KvetiRon 25: film-coated tablets, white in color, with a biconvex surface, round in shape.
KvetiRon 100: film-coated tablets, yellow in color, with a biconvex surface, round in shape, with a score line on one side.
KvetiRon 200: film-coated tablets, white in color, with a biconvex surface, round in shape, with a score line on one side.
Pharmacotherapeutic group.
Antipsychotic agents. ATC code N05A H04.
Pharmacological Properties.
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 affinity 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 Quetiron and its low propensity to cause extrapyramidal symptoms (EPS) compared to typical antipsychotics. Quetiapine and norquetiapine do not exhibit high affinity for benzodiazepine receptors, but they have high affinity for histamine and α1-adrenergic receptors and moderate affinity for α2-adrenergic receptors.
Quetiapine has low or no affinity for muscarinic cholinergic receptors, whereas norquetiapine has moderate to high affinity for several muscarinic receptor subtypes, which may explain the anticholinergic (muscarinic) effects.
Inhibition of the norepinephrine transporter (NET) by norquetiapine, as well as its partial agonist activity at 5HT1A receptors, may contribute to the therapeutic efficacy of Quetiron as an antidepressant.
Pharmacodynamics.
Quetiapine has been shown to be effective in tests of antipsychotic activity, such as conditioned avoidance response.
Quetiapine blocks the effects of dopamine agonists, as confirmed by behavioral assessments or electrophysiological studies, and increases the concentration of dopamine metabolites, providing neurochemical evidence of D2 receptor blockade.
In preclinical studies evaluating EPS, quetiapine demonstrated an atypical activity profile and differed from typical antipsychotics.
With prolonged use, quetiapine did not lead to supersensitivity of dopamine D2 receptors.
At doses effective for blocking dopamine D2 receptors, quetiapine caused only mild catalepsy.
Long-term administration of quetiapine has demonstrated selectivity for the limbic system and the ability to block depolarization of mesolimbic neurons, but not nigrostriatal dopaminergic neurons.
Pharmacokinetics.
Absorption.
After oral administration, quetiapine is well absorbed and undergoes extensive metabolism. Administration with food does not result in significant changes in quetiapine bioavailability.
At steady state, the maximum molar concentration of the active metabolite norquetiapine reaches approximately 35% of the quetiapine concentration.
The pharmacokinetics of quetiapine and norquetiapine within the approved dose range are linear.
Distribution.
Approximately 83% of quetiapine is protein-bound in plasma.
Metabolism.
Quetiapine is extensively metabolized in the liver. Studies using radiolabeled quetiapine have shown that less than 5% of the drug is excreted unchanged in urine or feces. In vitro studies have demonstrated that CYP3A4 is the primary enzyme of the cytochrome P450 family responsible for quetiapine metabolism. The formation and elimination of norquetiapine occur predominantly via the CYP3A4 isoenzyme. Approximately 73% of the radiolabeled compound is excreted in urine and 21% in feces.
Quetiapine and some of its metabolites (including norquetiapine) exhibit weak inhibitory effects in vitro on the cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4.
Inhibition of CYP isoenzymes in vitro occurred only at concentrations 5–50 times higher than those achieved with human doses in the range of 300–800 mg per day.
Based on these in vitro results, it is unlikely that co-administration of quetiapine with other active substances will lead to clinically significant inhibition of the metabolism of other drugs mediated by cytochrome P450. Animal studies have shown that quetiapine may induce cytochrome P450 enzymes. However, in a specific drug interaction study in patients with psychosis, no increase in cytochrome P450 activity was observed after quetiapine administration.
Elimination.
The elimination half-life of quetiapine and norquetiapine is approximately 7 hours and 12 hours, respectively. The mean molar fraction of free quetiapine and the active metabolite N-desalkylquetiapine excreted in urine is < 5% of the administered dose.
Special Populations.
Gender.
The pharmacokinetics of quetiapine in women and men are not different.
Elderly Patients.
The mean 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 < 30 mL/min/1.73 m²), the mean plasma clearance of quetiapine is reduced by approximately 25%, but individual clearance values remain within the range observed in healthy individuals.
Patients with Hepatic Impairment.
In patients with liver disease (compensated alcoholic cirrhosis), the mean 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, and therefore dose adjustment may be required for this patient group (see section "Dosage and Administration").
Children.
Pharmacokinetic data are available from children receiving 400 mg of quetiapine twice daily. At therapeutic doses, plasma levels of the parent compound quetiapine in children and adolescents (10–17 years) were generally similar to those in adults, although Cmax in children was higher than in adults. AUC and Cmax for norquetiapine were higher—approximately 62% and 49% in children (10–12 years), and 28% and 14% in adolescents (13–17 years), respectively—compared to adults.
Clinical characteristics.
Indications.
Schizophrenia.
Bipolar disorders, including:
- treatment of moderate to severe manic episodes in bipolar disorder;
- treatment of severe depressive episodes in bipolar disorder;
- prevention of relapse in patients with bipolar disorders in whom manic or depressive episodes have been treated with quetiapine.
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.
Kvetiron should be used with caution in combination with drugs acting on the central nervous system. Therefore, alcohol consumption is strictly prohibited during treatment.
Quetiapine should be used with caution in combination with serotonergic medicinal products such as monoamine oxidase inhibitors (MAO inhibitors), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, due to an increased risk of serotonin syndrome, a potentially life-threatening condition (see section "Special precautions for use").
The drug should be prescribed with caution to patients receiving other medications with anticholinergic (muscarinic) effects (see section "Special precautions for use").
Cytochrome P450 (CYP) 3A4 is the primary enzyme responsible for cytochrome P450-mediated metabolism of quetiapine. In a drug interaction study 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 treatment with quetiapine.
It is known that in a multiple-dose pharmacokinetic study evaluating quetiapine administered before and during treatment with carbamazepine (a hepatic microsomal 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, lower plasma concentrations of the drug may occur, which could affect the efficacy of quetiapine therapy.
Concomitant use of quetiapine and phenytoin (a hepatic microsomal enzyme inducer) results in an increase in quetiapine clearance by up to 450%. For patients taking a hepatic enzyme inducer, initiation of quetiapine therapy should only be considered if the physician determines that the benefit of using quetiapine outweighs the risks associated with discontinuation of the microsomal enzyme inducer. Importantly, any change in the inducer should be gradual and, if necessary, replaced with a drug that does not induce hepatic microsomal enzymes (e.g., sodium valproate).
Following concomitant administration of quetiapine with antidepressants such as imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor), no significant changes in quetiapine pharmacokinetics were observed.
The pharmacokinetics of quetiapine are not significantly altered when administered concomitantly with risperidone or haloperidol. Concomitant use of quetiapine and thioridazine results in an approximately 70% increase in quetiapine clearance.
The pharmacokinetics of quetiapine are not substantially altered when administered concomitantly with cimetidine, a cytochrome P450 inhibitor.
The pharmacokinetics of lithium are not altered when administered concomitantly with quetiapine.
It is known that in a 6-week randomized study comparing the combination of lithium and quetiapine versus placebo and quetiapine in adult patients suffering from 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 "Pharmacodynamics").
The pharmacokinetics of sodium valproate and quetiapine are not altered when administered concomitantly. It is known that in a retrospective study involving children and adolescents receiving sodium valproate, quetiapine, or a combination of these drugs, an increased incidence of leukopenia and neutropenia was observed in the group receiving both drugs compared to groups receiving either drug alone.
Studies on interactions with the most commonly used cardiovascular drugs have not been conducted.
Caution should be exercised when administering quetiapine concomitantly with medicinal products that disrupt electrolyte balance or prolong the QT interval.
In patients taking quetiapine, false-positive results in enzyme immunoassays for methadone and tricyclic antidepressants have been reported.
It is recommended to confirm questionable screening immunoassay results using a confirmatory chromatographic method.
Special precautions for use.
Since quetiapine is approved for several indications, the safety profile of the drug should be carefully considered with regard to the specific diagnosis established for a particular patient and the dose being administered.
Children
Quetiapine is not recommended for use in children and adolescents (under 18 years of age) due to the lack of data on use in this age group. Clinical studies of quetiapine have shown that, in addition to the known safety profile established for adults (see section "Adverse reactions"), the incidence of certain adverse events is higher in children than in adults (increased appetite, elevated serum prolactin levels, vomiting, rhinitis, and syncope), or may have different consequences in children and adolescents (extrapyramidal symptoms and irritability). Additionally, increased blood pressure has been observed, which was not previously reported in studies involving adult patients. Furthermore, changes in thyroid function parameters have been observed in children and adolescents.
It should also be noted that the long-term effects of quetiapine treatment on growth and sexual maturation have not been studied beyond 26 weeks. The long-term impact on cognitive and behavioral development is unknown.
It is known that in placebo-controlled clinical trials involving pediatric patients, treatment with quetiapine was associated with a higher incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and 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 few weeks of treatment or longer, patients should be closely monitored until such improvement occurs. According to general clinical experience, the risk of suicide may increase in the early stages of improvement. In addition, physicians should consider the potential risk of suicide-related events following abrupt discontinuation of quetiapine treatment due to known risk factors associated with the condition being treated.
Other psychiatric disorders for which quetiapine is prescribed may also be associated with an increased risk of suicide-related events. Moreover, these disorders may coexist with major depressive episodes. Therefore, the same precautions should be taken when treating other psychiatric disorders as are taken when treating major depressive episodes. Patients with a history of suicide-related events or those demonstrating a significant degree of suicidal thoughts prior to the start of treatment are at higher risk of suicidal thoughts or suicide attempts and require careful 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 with subsequent dose changes. Patients (and their caregivers) should be warned to monitor for clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek immediate medical help if symptoms occur.
In short-term placebo-controlled clinical trials involving patients with major depressive episodes in bipolar disorder, a higher risk of suicide-related events and manifestations was observed in young patients (under 25 years of age) treated with quetiapine compared to those receiving placebo (3% vs. 0%, respectively). A retrospective population analysis of quetiapine use in 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 when quetiapine was used in combination with other antidepressants.
Metabolic risk
Due to the identified risk of worsening metabolic profile, including changes in body weight, blood glucose (see "Hyperglycemia"), and lipids observed during 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 according to clinical relevance of the disorder (see section "Adverse reactions").
Extrapyramidal symptoms
It is known that in placebo-controlled trials, quetiapine use was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes associated with bipolar disorder (see section "Adverse reactions"). Quetiapine use has been associated with the development of akathisia, characterized by subjective distress or stress-inducing restlessness and an urge to move, often accompanied by an inability to sit or stand still. These phenomena are more likely to occur during the first few weeks of treatment. Increasing the dose in patients who develop such symptoms may be harmful.
Tardive dyskinesia
If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing quetiapine. Symptoms of tardive dyskinesia may worsen or even emerge 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 (see section "Adverse reactions"). Clinical trials have reported that such symptoms in patients with bipolar depression typically occur within the first 3 days of treatment and are mostly 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.
Orthostatic hypotension
Treatment with quetiapine has been associated with orthostatic hypotension and related dizziness (see section "Adverse reactions"), which, like somnolence, usually occur during the initial dose titration period. These effects may contribute to an increased frequency of accidental injuries (falls), especially among elderly patients. Therefore, patients should be advised to be cautious until they become accustomed to the possible effects of the drug.
Quetiapine should be used with caution in patients with 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. Therefore, quetiapine should be used cautiously in patients with a history of sleep apnea, patients with excessive body weight/obesity, male patients, and patients receiving concomitant therapy with drugs that suppress the central nervous system.
Seizures
In controlled clinical trials, no difference in seizure frequency was observed between patients taking quetiapine and those receiving placebo. There are no data on seizure occurrence in patients with a history of epilepsy. As with other antipsychotic drugs, caution is recommended when treating patients with a history of seizures (see section "Adverse reactions").
Malignant neuroleptic syndrome
Malignant neuroleptic syndrome has been associated with treatment with antipsychotic drugs, including quetiapine (see section "Adverse reactions"). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic instability, and increased creatine phosphokinase levels. In such cases, quetiapine treatment should be discontinued and appropriate medical treatment initiated.
Serotonin syndrome
Concomitant use of Quetiron and other serotonergic drugs, such as monoamine oxidase inhibitors (MAO inhibitors), 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 drugs is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and with 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 in quetiapine studies, severe neutropenia (neutrophil count < 0.5×10⁹/L) occurred infrequently. Most cases of severe neutropenia occurred within several months after starting quetiapine treatment. A clear dose-dependent relationship was not observed. In post-marketing studies, some cases were fatal. Possible risk factors for developing neutropenia include a previous history of low white blood cell count and a history of neutropenia caused by any drug. However, some cases occurred in patients without pre-existing risk factors. Treatment with quetiapine should be discontinued in patients with neutrophil count < 1×10⁹/L. Patients should be monitored for possible signs and symptoms of infection and for neutrophil count (until the count exceeds 1.5×10⁹/L).
Neutropenia should be considered in patients with infection and fever, especially in the absence of obvious predisposing factor(s), and appropriate clinical measures should be taken. Patients should be advised to immediately report symptoms consistent with agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during quetiapine treatment. Such patients should promptly undergo white blood cell count and absolute neutrophil count (ANC) determination, especially in the absence of predisposing factors.
Anticholinergic (muscarinic) syndrome
Norquetiapine, an active metabolite of quetiapine, has moderate to high affinity for several subtypes of muscarinic receptors. This contributes to the occurrence of adverse reactions reflecting anticholinergic effects when quetiapine is used at recommended doses, when quetiapine is used concomitantly with other drugs having anticholinergic effects, or in cases of overdose. Quetiapine should be used with caution in patients receiving drugs with anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with urinary disorders (urinary retention), significant prostatic 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 inducer of hepatic microsomal enzymes, such as carbamazepine or phenytoin, significantly reduces quetiapine plasma concentrations, which may reduce the effectiveness of quetiapine therapy.
Patients receiving microsomal enzyme inducers should only start quetiapine treatment if the physician considers the benefit of using quetiapine to outweigh the risk of discontinuing the microsomal enzyme inducer. It is important that changes in treatment with such inducers are made gradually, and if necessary, replaced with a non-inducer (e.g., sodium valproate).
Body weight
Cases of increased body weight have been observed in patients treated with quetiapine, and therefore body weight should be monitored and corrected as clinically necessary according to appropriate recommendations for antipsychotic agents (see section "Adverse reactions").
Hyperglycemia
In rare cases, hyperglycemia and/or the development or worsening of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, including several fatal cases, have been reported (see section "Adverse reactions"). In some cases, these events occurred in patients with increased body weight, which could be a predisposing factor. Adequate clinical monitoring according to appropriate recommendations for antipsychotic agents is recommended. Patients receiving any antipsychotic agent, including quetiapine, should be monitored for possible signs and symptoms of hyperglycemia (such as polydipsia, polyuria, 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
Elevations in triglycerides, low-density lipoprotein (LDL), and total cholesterol, as well as decreases in high-density lipoprotein (HDL) cholesterol levels (see section "Adverse reactions"). Lipid changes should be managed according to clinical indications.
QT interval prolongation
In clinical trials and when used according to the instructions for medical use, quetiapine administration was not associated with a sustained increase in the absolute QT interval. In post-marketing use, QT interval prolongation has been reported with therapeutic doses (see section "Adverse reactions") and in cases of overdose (see section "Overdose"). As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases or patients with a family history of prolonged QT interval. Caution is necessary when prescribing quetiapine, as with other neuroleptic agents, concomitantly with drugs that prolong the QT interval (see section "Interaction with other medicinal products and other types of interactions"), especially in elderly patients, patients with congenital long QT syndrome, heart failure, cardiac hypertrophy, hypokalemia or hypomagnesemia, and patients with a family history of prolonged QT interval.
Cardiomyopathy and myocarditis
Cases of cardiomyopathy and myocarditis have been reported in clinical trials and post-marketing surveillance (see section "Adverse reactions"). In patients suspected of having cardiomyopathy or myocarditis, consideration should be given to discontinuing quetiapine treatment.
Severe skin adverse reactions
During quetiapine treatment, very rare cases of severe skin adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported.
Severe skin adverse reactions usually present with one or more of the following 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 reported within 6 weeks after starting quetiapine therapy. If signs and symptoms suggestive of these severe skin reactions appear, quetiapine should be immediately discontinued and alternative treatment options considered.
Discontinuation of treatment
Abrupt discontinuation of quetiapine may result in an acute withdrawal syndrome characterized by insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. Therefore, it is recommended to discontinue the drug gradually over at least one to two weeks (see section "Adverse reactions").
Elderly patients with psychosis associated with dementia
Quetiapine is not recommended for the treatment of patients with psychosis associated with dementia. In randomized placebo-controlled trials in patients with dementia, the use of some atypical antipsychotics was associated with approximately a threefold increased risk of cerebrovascular adverse events. The mechanism of this increased risk remains unknown. An increased risk cannot be excluded with the use of other antipsychotics or in other patient groups. Quetiapine should be used with caution in patients with risk factors for stroke.
According to a meta-analysis of atypical antipsychotics, elderly patients with psychosis associated with dementia represent a group at increased risk of fatal outcome from the use of these drugs compared to placebo. However, data from two 10-week placebo-controlled trials of quetiapine in similar populations (n=710, 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 occurred from various causes expected in this patient population.
Elderly patients with Parkinson's disease (PD)/parkinsonism
It is known that in a retrospective study of quetiapine for the treatment of patients with major depressive disorder (MDD), an increased risk of mortality with quetiapine use was observed in patients over 65 years of age. These data were absent when patients with Parkinson's disease were excluded from the analysis. Caution should be exercised when prescribing quetiapine to elderly patients with Parkinson's disease.
Dysphagia
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 intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with quetiapine use (see section "Adverse reactions"). These reports include fatal cases in patients at higher risk of intestinal obstruction, including those receiving multiple drugs that reduce intestinal motility and/or drugs for which constipation symptoms may not have been previously reported. Patients with intestinal obstruction/constipation should be closely monitored and provided with emergency care if necessary.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic drugs 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 during clinical trials and post-marketing use. Marketing reports indicated that many, although not all, 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 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.
Misuse and abuse
Cases of misuse and abuse of the drug have been reported. Quetiapine should be prescribed with caution to patients with a history of alcohol or substance abuse.
The drug contains lactose; therefore, patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.
Use during pregnancy or breastfeeding.
Pregnancy
First trimester
A moderate amount of published data on pregnancy exposure (i.e., from 300 to 1000 pregnancy outcomes), including individual reports and some observational studies, does not indicate an increased risk of developmental malformations due to quetiapine treatment. However, based on all available data, a definitive conclusion cannot be drawn. Animal studies have shown reproductive toxicity. Thus, quetiapine should be used during pregnancy only if the benefit justifies the potential risk.
Third trimester
The use of antipsychotic drugs (including quetiapine) during the third trimester of pregnancy may lead to adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after birth. Reports include agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders. Therefore, newborns whose mothers were treated with quetiapine during the third trimester of pregnancy should be closely monitored.
Period of breastfeeding
Based on very limited data from published reports on the excretion of quetiapine in human breast milk, excretion of quetiapine at therapeutic doses is uncertain. Due to the lack of reliable data, a decision should be made whether to discontinue breastfeeding or discontinue quetiapine therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
The effect of quetiapine on human fertility has not been evaluated. It is known that in rat studies, effects related to elevated prolactin levels were observed, although they are not directly relevant to humans.
Ability to affect reaction speed when driving or operating machinery.
Since the drug primarily affects the central nervous system, quetiapine may adversely affect activities requiring concentration. Therefore, patients should be advised to avoid driving or operating machinery until their individual sensitivity to this effect is determined.
Method of administration and dosing.
There are different dosages for each indication. The dose of the medication and the duration of treatment are determined individually by a physician for each patient depending on the indication and severity of the disease.
For oral use.
Quetiapine may be taken regardless of food intake.
Adults.
Treatment of schizophrenia.
Quetiapine should be taken twice daily.
During the first 4 days of therapy, the daily dose is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg. Starting from Day 4, the dose should be increased until the desired clinical effect is achieved (within the range of 300 to 450 mg/day). Depending on clinical efficacy and tolerability, the daily dose of Quetiron may range from 150 mg to 750 mg.
Treatment of moderate to severe manic episodes in bipolar disorder.
Quetiapine should be taken twice daily.
The daily dose during the first 4 days of treatment is: Day 1 – 100 mg, Day 2 – 200 mg, Day 3 – 300 mg, Day 4 – 400 mg. Thereafter, the dose should be increased (but not more than 200 mg per day) up to 800 mg/day by Day 6 of treatment. Depending on clinical efficacy and tolerability, the dose may range from 200 to 800 mg/day. The usual effective dose is within the range of 400 to 800 mg daily.
Treatment of major depressive episodes associated with bipolar disorders.
Quetiapine should be administered once daily at bedtime.
The daily dose during the first 4 days of treatment is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg. The recommended daily dose is 300 mg. Clinical studies have shown no additional benefit with the 600 mg dose compared to the 300 mg dose. The 600 mg dose may be effective in some patients. Clinical studies indicate that for some patients experiencing tolerability issues, the dose may be reduced to the minimum of 200 mg. Doses exceeding 300 mg should be prescribed only by a physician experienced in the treatment of bipolar disorder.
Prevention of relapse in patients with bipolar disorders.
To prevent recurrence of manic, depressive, or mixed episodes in bipolar disorder, patients who have responded to quetiapine during acute treatment should continue therapy at the same dose. The dose may be adjusted according to the individual patient's clinical response and tolerability within the daily dose range of 300 mg to 800 mg, administered twice daily. It is important that the lowest effective doses are used for maintenance therapy.
Elderly patients.
Quetiapine, like other antipsychotic agents, should be prescribed with caution in elderly patients, especially at the beginning of treatment. A slower dose titration may be necessary, and the daily therapeutic dose should generally be lower than that used in younger patients, depending on the individual patient's clinical response and tolerability. Mean plasma clearance of quetiapine was reduced by 30–50% in elderly patients compared to younger patients.
Efficacy and safety have not been evaluated in patients over 65 years of age with depressive episodes in the context of bipolar disorder.
Renal impairment.
Dose adjustment is not required in patients with renal impairment.
Hepatic impairment.
Quetiapine is extensively metabolized in the liver; therefore, Quetiron should be used with caution in patients with hepatic impairment, especially during initial treatment.
Patients with hepatic impairment should start at a dose of 25 mg/day. The dose should be increased by 25–50 mg/day daily until an effective dose is reached, depending on clinical response and patient tolerability.
Children.
There is insufficient data on the safety and efficacy of quetiapine to support its use in children; therefore, quetiapine should not be used in pediatric practice.
Overdose.
Symptoms.
Manifestations and symptoms of overdose are due to the exaggerated known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, hypotension, and anticholinergic effects.
Overdose may lead to QT interval prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and/or agitation, coma, and fatal outcome.
Patients with pre-existing severe cardiovascular disease may have an increased risk of overdose effects (see section "Special precautions").
Treatment.
There is no specific antidote. In cases of significant intoxication, intensive symptomatic and supportive therapy is required, including maintenance and monitoring of airway patency, adequate ventilation and oxygenation, and cardiovascular function.
According to published literature, patients with delirium, agitation, and pronounced anticholinergic syndrome may be treated with physostigmine (1–2 mg) under continuous ECG monitoring. However, this treatment is not recommended as standard due to the negative effects of physostigmine on cardiac conduction. Physostigmine may be used only when there are no ECG abnormalities. Physostigmine should not be used in the presence of arrhythmias, any degree of heart block, or QRS complex widening.
Although prevention of absorption has not been studied in quetiapine overdose, gastric lavage (within 1 hour of ingestion) and administration of activated charcoal may be considered in cases of severe overdose.
In cases of quetiapine overdose with persistent hypotension, appropriate measures such as intravenous fluid administration and/or sympathomimetic agents should be taken.
Adrenaline (epinephrine) and dopamine should be avoided, as beta-stimulation may worsen hypotension under alpha-blockade induced by quetiapine.
Careful medical monitoring should continue until the patient has fully recovered.
Adverse Reactions
The most commonly observed adverse reactions during quetiapine administration include: somnolence, dizziness, dry mouth, headache, withdrawal syndrome, elevated serum triglyceride levels, increased total serum cholesterol levels (predominantly LDL-C), decreased HDL-C cholesterol levels, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms.
The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated based on available data).
Blood and lymphatic system disorders: very common – decreased hemoglobin22; common – leukopenia1,28, decreased neutrophil count, increased eosinophil levels27; 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 – disturbance in antidiuretic hormone secretion.
Metabolism and nutrition disorders: very common – increased serum triglycerides10,30, increased total cholesterol (particularly LDL-C)11,30, decreased high-density lipoprotein (HDL) levels17,30, weight gain8,30; common – increased appetite, increased glucose levels reaching hyperglycemic ranges6,30; uncommon – hyponatremia19, diabetes mellitus1,5, worsening of diabetes; rare – metabolic syndrome29.
Psychiatric disorders: common – unusual dreams, nightmares, suicidal thoughts and behavior20; rare – sleepwalking and related events such as talking during sleep 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, confusion.
Cardiac disorders: common – tachycardia4, palpitations23; uncommon – QT interval prolongation1,12,18, bradycardia32; frequency not known – cardiomyopathy, 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/volvulus.
Hepatobiliary disorders: common – increased transaminase levels (alanine aminotransferase3, gamma-glutamyl transferase3); uncommon – increased aspartate aminotransferase levels3; 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 disturbances.
General disorders: very common – withdrawal symptoms1,9; common – mild asthenia, peripheral edema, irritability, hyperthermia; rare – neuroleptic malignant syndrome1, hypothermia.
Investigations: rare – increased creatine phosphokinase levels14.
Footnotes:
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 elevations (shift from normal to >3×ULN at any time) in transaminase levels (ALT, AST) or gamma-GT (glutamyl transferase) have been observed in some patients treated with quetiapine. These elevations were generally reversible with continued quetiapine treatment.
4 – as with other antipsychotics that block α1-adrenergic receptors, quetiapine frequently causes orthostatic hypotension, accompanied by dizziness, tachycardia, and in some patients, syncope, particularly during the initial dose titration period (see section "Special precautions for use").
5 – frequency estimates for these adverse reactions were derived only from post-marketing data of quetiapine use in the immediate-release formulation.
6 – fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or postprandial blood glucose ≥200 mg/dL (≥11.1 mmol/L), at least once.
7 – increased incidence of dysphagia with quetiapine compared to placebo was observed only in clinical trials of bipolar depression.
8 – based on >7% increase in body weight from baseline. Occurs 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 significantly decreased within one week after discontinuation.
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. Increases in LDL-C cholesterol ≥30 mg/dL (≥0.769 mmol/L) occurred very commonly. The mean increase among patients with such elevations was 41.7 mg/dL (1.07 mmol/L).
12 – see text below.
13 – platelets ≤100×109/L at least once.
14 – based on adverse reaction reports from clinical trials, elevated creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.
15 – prolactin level (patients >18 years): >20 µg/L (>869.56 pmol/L) in males; >30 µg/L (>1304.34 pmol/L) in females – at any time.
16 – may lead to falls.
17 – HDL-C 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 an increase ≥30 msec. In placebo-controlled quetiapine trials, mean changes and the number of patients with shifts to clinically significant levels were similar in quetiapine and placebo groups.
19 – shift from >132 mmol/L to ≤132 mmol/L at least once.
20 – cases of suicidal thoughts and suicidal behavior were reported during quetiapine therapy or immediately after discontinuation (see sections "Special precautions for use" and "Pharmacological properties").
21 – see section "Pharmacological properties".
22 – decrease in hemoglobin 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 patients treated with quetiapine across all studies including open-label trials. The mean maximum decrease in hemoglobin at any time for these patients was 1.50 g/dL.
23 – these events often occurred in the context of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disease.
24 – based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Deviation for total T4, free T4, total T3, and free T3 was <0.8×ULN (pmol/L), and for TSH >5 mU/L at any time.
25 – based on increased frequency of vomiting in elderly patients (≥65 years).
26 – deviation of neutrophil count from ≥1.5×109/L baseline to <0.5×109/L at any time during treatment.
27 – based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Eosinophil deviation was >1×109 cells/L at any time.
28 – based on deviation from normal baseline to potentially clinically significant values at any time after baseline in all studies. Leukocyte deviation was ≤3×109 cells/L at any time.
29 – based on adverse reaction reports of metabolic syndrome from all clinical trials of quetiapine.
30 – during clinical trials, some patients experienced worsening of more than one metabolic factor affecting body weight, blood glucose, and lipids (see section "Special precautions for use").
31 – see section "Use in pregnancy or breastfeeding".
32 – may occur during or shortly after initiation of therapy and may be associated with hypotension and/or syncope. Frequency is based on adverse reaction reports of bradycardia and related events observed in all clinical trials of quetiapine.
33 – based on one retrospective non-randomized epidemiological study.
With antipsychotics, very rare cases of QT interval prolongation on ECG, ventricular arrhythmia, polymorphic ventricular tachycardia (torsade de pointes), sudden unexplained death, and cardiac arrest have been reported. These effects are considered class-specific.
Serious cutaneous 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. The table below summarizes adverse reactions with higher incidence in this patient age group or not observed in adults.
Frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <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 – syncope.
Vascular disorders: very common – increased blood pressure2.
Respiratory, thoracic and mediastinal disorders: common – rhinitis.
Gastrointestinal disorders: very common – vomiting.
General disorders: common – irritability3.
Footnotes:
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 deviation above clinically significant thresholds (adapted from National Institutes of Health criteria) or increase >20 mmHg for systolic or >10 mmHg for diastolic blood pressure at any time, derived from short-term (3–6 weeks) placebo-controlled trials in children and adolescents.
3 – note: frequency corresponds to that observed in adults, but irritability may manifest differently in children and adolescents compared to adults.
4 – see section "Pharmacological properties".
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Shelf life
3 years.
Do not use the medicinal product after the expiry date stated on the packaging.
Storage conditions
Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25°C.
Packaging
Kvethiron 25: 30 tablets in a blister; 1 blister in a cardboard pack;
Kvethiron 100: 10 tablets in a blister; 1, 3, or 6 blisters per cardboard pack;
Kvethiron 200: 10 tablets in a blister; 1, 3, or 6 blisters per cardboard pack.
Prescription status
Prescription only.
Manufacturer
LLC "Pharma Start".
Manufacturer's address and place of business
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.