Kvetimak 100

INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT Quetimac 25/Quetimac 25 Quetimac 100/Quetimac 100 Quetimac 200/Quetimac 200 Composition: active substance: quetiapine; 1 film-coated tablet contains quetiapine fumarate equivalent to 25 mg or 100 mg or 200 mg of quetiapine respectively; excipients: dosage 25 mg: microcrystalline cellulose; calcium hydrogen phosphate; lactose monohydrate; sodium starch glycolate; povidone; colloidal anhydrous silicon dioxide; magnesium stearate; coating Opadry Pink 03B84643: hypromellose; titanium dioxide (E 171); macrogol; yellow iron oxide (E 172); red iron oxide (E 172). dosage 100 mg: microcrystalline cellulose; calcium hydrogen phosphate; lactose monohydrate; sodium starch glycolate; povidone; colloidal anhydrous silicon dioxide; magnesium stearate; coating Opadry Yellow 03B82459: hypromellose; titanium dioxide (E 171); macrogol; yellow iron oxide (E 172). dosage 200 mg: microcrystalline cellulose; calcium hydrogen phosphate; lactose monohydrate; sodium starch glycolate; povidone; colloidal anhydrous silicon dioxide; magnesium stearate; coating Opadry White Y-1-7000: hypromellose; titanium dioxide (E 171); macrogol. Medicinal form. Film-coated tablets. Main physicochemical properties: - 25 mg tablets: round film-coated tablets, peach-colored, with "F 71" engraved on one side and smooth surface on the other side; - 100 mg tablets: round film-coated tablets, yellow-colored, with "F 73" engraved on one side and smooth surface on the other side; - 200 mg tablets: round film-coated tablets, white-colored, with "F 75" engraved on one side and smooth surface on the other side. Pharmacotherapeutic group. Antipsychotics. Quetiapine. ATC code N05A H04. Pharmacological properties. Pharmacodynamics. Mechanism of action. Quetiapine is an atypical antipsychotic medicinal product. Quetiapine and its active metabolite N-desalkylquetiapine (norquetiapine) interact with a broad spectrum of central nervous system neurotransmitter receptors. Quetiapine and the active metabolite in human plasma, norquetiapine, interact with a broad spectrum of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1 and D2 receptors. This combination of receptor antagonism with higher selectivity for 5HT2 versus D2 receptors is believed to contribute to the clinical antipsychotic properties of quetiapine and its low likelihood of extrapyramidal disorders compared to typical antipsychotics. Quetiapine and norquetiapine have no significant affinity for benzodiazepine receptors, but high affinity for histaminergic and alpha1 adrenergic receptors and moderate affinity for alpha2 adrenergic receptors. Quetiapine also has low or no affinity for muscarinic receptors, whereas norquetiapine has moderate to high affinity for several muscarinic receptors, which may explain anticholinergic (muscarinic) effects. The inhibitory effect on neuronal excitability and partial affinity for serotonin 5HT1A receptors of norquetiapine may contribute to the therapeutic efficacy of quetiapine as an antidepressant. Pharmacodynamic effects. Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists as measured behaviorally or electrophysiologically, and increases the concentration of the dopamine metabolite, a neurochemical index of D2 receptor blockade. In preclinical tests involving extrapyramidal disorders, quetiapine has an atypical profile unlike typical antipsychotics. Quetiapine does not cause dopamine D2 receptor hypersensitivity after chronic administration. Quetiapine causes only mild catalepsy at effective doses of dopamine D2 receptor blockade. Quetiapine demonstrates selectivity for the limbic system, producing blockade of mesolimbic but not nigrostriatal dopaminergic neurons after chronic administration. Quetiapine demonstrates minimal dystonic response in haloperidol-sensitized or drug-naive Cebus monkeys after acute and chronic administration. Pharmacokinetics Absorption Quetiapine is well absorbed and extensively metabolized after oral administration. Food intake does not significantly affect the bioavailability of quetiapine. Peak molar concentrations of the active metabolite norquetiapine at steady state are 35% of those observed for quetiapine. The pharmacokinetics of quetiapine and norquetiapine are linear within the approved dosage range. Distribution Quetiapine is approximately 83% bound to plasma proteins. Biotransformation Quetiapine is extensively metabolized in the liver, with the parent compound accounting for less than 5% of unchanged drug-related substance in urine or feces after administration of radiolabeled quetiapine. In vitro studies have established that CYP3A4 is the primary enzyme responsible for cytochrome P450-mediated metabolism of quetiapine. Norquetiapine is predominantly formed and eliminated via CYP3A4. Approximately 73% of radioactivity is excreted in urine and 21% in feces. It has been established that quetiapine and several of its metabolites (including norquetiapine) are weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 activity in vitro. In vitro inhibition of cytochrome enzymes is observed only at concentrations approximately 5–50 times higher than those observed in the dose range of 300–800 mg per day in humans. Based on these in vitro results, it is unlikely that concomitant administration of quetiapine with other drugs will lead to clinically significant inhibition of cytochrome P450 metabolism. Animal studies indicate that quetiapine may induce cytochrome P450 enzymes. However, in a specific interaction study in psychotic patients, no increase in cytochrome P450 activity was observed after quetiapine administration. Elimination The elimination half-life of quetiapine and norquetiapine is approximately 7 and 12 hours, respectively. The fraction of the average molar dose of free quetiapine and the active human metabolite norquetiapine excreted in urine is < 5%. Population characteristics Sex The pharmacokinetics of quetiapine in women and men do not differ. Elderly subjects The average clearance of quetiapine in elderly subjects is approximately 30–50% lower than in adults aged 18–65 years. Renal impairment The average plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m²), but individual clearance values were within the range for normal subjects. Hepatic impairment The average plasma clearance of quetiapine is reduced by approximately 25% in subjects with known liver impairment (stable alcoholic cirrhosis). Since quetiapine is extensively metabolized by the liver, elevated plasma levels are expected in the population with liver impairment. Dose adjustment may be required in these patients. Pediatrics Pharmacokinetic data were collected in 9 children aged 10–12 years and 12 adolescents hospitalized at a dose of 400 mg twice daily. At steady state, normalized plasma doses of the parent compound, quetiapine, in children and adolescents (10–17 years) were generally similar to adults, although Cmax in children was in the upper range observed in adult subjects. AUC and Cmax for the active metabolite, norquetiapine, were higher, approximately 62% and 49% in children (10–12 years), respectively 28% and 14% in adolescents (13–17 years), compared to adults. Clinical characteristics. Indications Treatment of schizophrenia. Treatment of bipolar disorder:

• for treatment of moderate and severe manic episodes in bipolar disorder.
• for treatment of major depressive episodes in bipolar disorder.
• for prevention of recurrence of manic or depressive episodes in patients with bipolar disorder who have previously responded to quetiapine treatment.

Contraindications. Hypersensitivity to the active substance or to any component of the product. Concomitant use of cytochrome P450 3A4 inhibitors such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin, and nefazodone is contraindicated. Interaction with other medicinal products and other types of interactions. Since quetiapine primarily affects the central nervous system, Quetimac should be used with caution in combination with other agents having similar effects and with alcohol. Quetiapine should be used with caution together with serotonergic medicinal products such as MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, as the risk of developing serotonin syndrome, a potentially life-threatening condition, is increased (see section "Special precautions for use"). Cytochrome P450 (CYP) 3A4 is the enzyme primarily responsible for the metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (25 mg) with ketoconazole (a CYP 3A4 inhibitor) resulted in a 5–8 fold increase in AUC of quetiapine. Therefore, concomitant use of quetiapine with CYP 3A4 inhibitors is contraindicated. Grapefruit juice should also not be consumed during the period of quetiapine treatment. In a multiple-dose study to assess the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant use of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic exposure to quetiapine (measured as AUC) to a level averaging 13% of exposure during quetiapine alone, although a greater effect was observed in some patients. Due to this interaction, lower plasma concentrations may occur, which may affect the efficacy of Quetimac therapy. Concomitant use of quetiapine and phenytoin (another microsomal enzyme inducer) resulted in an increase in quetiapine clearance of approximately 450%. Initiation of Quetimac therapy in patients receiving a hepatic enzyme inducer should only be considered if the physician considers the benefit of Quetimac use to outweigh the risks associated with discontinuation of the hepatic enzyme inducer. It is important that any changes in the use of the inducer be gradual. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate) (see section "Special precautions for use"). The pharmacokinetics of quetiapine are not significantly altered by concomitant use of antidepressants such as imipramine (a known CYP 2D6 inhibitor) or fluoxetine (a known CYP 3A4 and CYP 2D6 inhibitor). Concomitant use of antipsychotics such as risperidone or haloperidol did not cause significant changes in the pharmacokinetics of quetiapine. Concomitant use of quetiapine and thioridazine resulted in an increase in quetiapine clearance of approximately 70%. When used concomitantly with cimetidine, the pharmacokinetics of quetiapine were unchanged. The pharmacokinetics of lithium were unchanged when used concomitantly with quetiapine. In a 6-week randomized study comparing the combination of lithium with Quetimac and placebo with Quetimac in adult patients suffering from acute mania, an increased frequency of extrapyramidal events (especially tremor), somnolence, and weight gain was observed in the group receiving lithium compared to the placebo group (see section "Pharmacological properties"). No clinically significant changes in the pharmacokinetics of sodium valproate and quetiapine were observed when used concomitantly. 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 these drugs separately. Interaction studies with cardiovascular drugs have not been conducted. Caution should be exercised when using quetiapine concomitantly with drugs that disrupt electrolyte balance or prolong the QT interval. Patients receiving quetiapine have experienced false positive results in enzyme immunoassays for methadone and tricyclic antidepressants. It is recommended to verify questionable screening immunoassay results using an appropriate chromatographic method. Special precautions for use. Since Quetimac has several indications, the safety profile should be considered in relation to the patient's diagnosis and the dose administered. Children Quetiapine is not recommended for use in children and adolescents under 18 years of age due to lack of data confirming use in this age group. Clinical trials with quetiapine have shown that in addition to the known safety profile observed in adults, certain adverse events occurred more frequently in children and adolescents compared to adults (increased appetite, increased serum prolactin levels, vomiting, rhinitis, and syncope), or may have different consequences for children and adolescents (extrapyramidal symptoms and irritability), and one not previously observed in adult studies (increased blood pressure). Changes in thyroid function tests were also observed in children and adolescents. The delayed effect of Quetimac treatment on growth and sexual maturation has not been studied for periods longer than 26 weeks. The long-term effect on cognitive and behavioral development is unknown. During placebo-controlled clinical trials of Quetimac involving pediatric and adolescent patients, quetiapine treatment was associated with a higher frequency of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania, and bipolar depression (see section "Adverse reactions"). Suicide/suicidal thoughts or clinical worsening Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until a marked remission is established. Since improvement may not be observed 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 improvement. In addition, the potential risk of suicide-related events after abrupt discontinuation of quetiapine treatment should be considered due to known risk factors of the disease being treated. Other psychiatric disorders for which Quetimac is prescribed may also be associated with an increased risk of suicide-related events. Moreover, these disorders may co-occur with depressive episodes. Therefore, the same precautions taken when treating patients with major depressive episodes should be applied when treating patients with other psychiatric disorders. Patients with a history of suicide-related events or who demonstrate significant levels of suicidal thinking before the start of therapy have a higher risk of developing suicidal thoughts or suicide attempts and should be under close supervision during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior compared to placebo in patients under 25 years of age. Close monitoring of patients, particularly those at high risk, should accompany pharmacological therapy, especially at the beginning of treatment and with subsequent dose changes. Patients (and 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 these symptoms occur. In short-term placebo-controlled trials involving patients with severe 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). A population retrospective study of quetiapine for the treatment of patients with major depressive disorder showed an increased risk of self-harm and suicide in patients aged 25 to 64 years without a history of self-harm during quetiapine use with other antidepressants. Metabolic risk Given the observed risk of worsening metabolic profile, including changes in weight, blood glucose levels (see hyperglycemia) and lipids observed in clinical trials, metabolic parameters of patients should be assessed at the start of treatment and changes in these parameters should be regularly monitored during the course of treatment. Worsening of these parameters should be managed according to clinical requirements. Extrapyramidal symptoms In placebo-controlled trials in adult patients, quetiapine was associated with an increased frequency of extrapyramidal symptoms (EPS) compared to placebo in patients receiving treatment for major depressive episodes associated with bipolar disorder. Quetiapine use was associated with the development of akathisia, characterized by subjectively unpleasant or distressing restlessness and a need to move, often accompanied by 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 symptoms of tardive dyskinesia occur, the need to reduce the dose or discontinue Quetimac should be considered. Symptoms of tardive dyskinesia may worsen and even occur after discontinuation of therapy (see section "Adverse reactions"). Somnolence and dizziness Quetiapine treatment is associated with somnolence and similar symptoms such as sedation (see section "Adverse reactions"). In clinical trials of treatment of patients with bipolar depression, these symptoms typically occurred within the first 3 days of treatment and were mostly mild to moderate in intensity. Patients who experience somnolence may require monitoring for 2 weeks after the onset of somnolence or until symptoms resolve and may need to consider discontinuation of treatment. Orthostatic hypotension Quetiapine treatment has been associated with orthostatic hypotension and related dizziness, which, like somnolence, usually occur during the initial dose titration period. This may lead to an increased frequency of accidental injuries (falls), especially in elderly individuals. Therefore, patients should be advised to be cautious until they become familiar with the potential effects of the medicinal product. Quetiapine should be used with caution in patients with established cardiovascular or cerebrovascular diseases or other conditions that may lead to hypotension. Dose reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease. Sleep apnea syndrome Cases of sleep apnea syndrome have been reported in patients taking quetiapine. Quetiapine should be used with caution in patients who are concurrently receiving central nervous system depressants and have a history of sleep apnea or are at risk. This includes, in particular, patients who are overweight/obese or male patients. Seizures During controlled clinical trials, there was no difference in the frequency of seizures between patients taking quetiapine and patients in the placebo group. There are no data on the frequency of seizures in patients with seizure disorders. As with treatment with other antipsychotic agents, it is recommended to use the product with caution in patients with a history of seizures (see section "Adverse reactions"). Neuroleptic malignant syndrome Neuroleptic malignant syndrome may be associated with antipsychotic treatment, including quetiapine. Clinical manifestations include hyperthermia, changes in mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase levels. In such cases, Quetimac should be discontinued and appropriate medical treatment initiated. Serotonin syndrome Concomitant use of quetiapine fumarate 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 the development of serotonin syndrome – a potentially life-threatening condition (see section "Interaction with other medicinal products and other types of interactions"). If concomitant treatment with other serotonergic medicinal products is clinically justified, careful monitoring of the patient is recommended, 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, dose reduction or discontinuation of therapy should be considered depending on the severity of symptoms. Severe neutropenia and agranulocytosis Severe neutropenia (neutrophil count < 0.5 × 10⁹/l) was infrequently observed in clinical trials of quetiapine. Agranulocytosis (severe neutropenia with infection) was rarely reported in patients receiving quetiapine during clinical trials and post-marketing use (including fatal cases). Most cases of severe neutropenia occurred within two months of starting quetiapine therapy. No clear dose relationship was established. During the post-marketing period, normalization of white blood cell and/or neutrophil counts occurred after discontinuation of quetiapine therapy. Possible risk factors for neutropenia include low white blood cell count and drug-induced neutropenia in history. Cases of agranulocytosis occurred in patients without risk factors. The possibility of neutropenia should be considered in patients with infection, especially without obvious factors, and in patients with fever of unknown origin, and appropriate clinical measures should be applied. It is recommended to discontinue quetiapine treatment if neutrophil count in blood is < 1.0 × 10⁹/l. Monitoring of patients for signs and symptoms of infection and neutrophil count (until they exceed < 1.5 × 10⁹/l) is recommended (see section "Pharmacological properties"). In clinical trials of quetiapine, severe neutropenia (neutrophil count < 0.5 × 10⁹/l) was reported. Most cases of severe neutropenia occurred within several months of starting quetiapine therapy. No obvious dose dependence was observed. In post-marketing experience, some cases had a fatal outcome. Possible risk factors for neutropenia include pre-existing low white blood cell count and history of drug-induced neutropenia. However, some cases occurred in patients without pre-existing risk factors. Quetiapine should be discontinued in patients with neutrophil count < 1.0 × 10⁹/l. Patients should be monitored for signs and symptoms of infection and neutrophil count (until they exceed 1.5 × 10⁹/l) (see section "Pharmacological properties"). The possibility of neutropenia should be considered in patients with infection or fever, especially without obvious factors, and appropriate clinical measures should be applied. Patients should be advised to immediately report signs (symptoms) indicative of agranulocytosis or infection (e.g., fever, weakness, lethargy, or sore throat) at any time during Quetimac therapy. Such patients should immediately undergo monitoring of white blood cell count and absolute neutrophil count (ANC), especially without influencing factors. Anticholinergic (muscarinic) effects Norquetiapine, the active metabolite of quetiapine, has moderate to strong affinity for several subtypes of muscarinic receptors. This affects ADRs, reflecting anticholinergic effects when quetiapine is used at recommended doses, concomitantly with other anticholinergic drugs, and in cases of overdose. Quetiapine should be used with caution in patients receiving drugs with anticholinergic (muscarinic) effects. Quetiapine should be used with caution in patients with a current diagnosis or history of urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or related conditions, increased intraocular pressure or closed-angle glaucoma. Cardiovascular diseases Quetimac should be used with caution in patients with cardiovascular and cerebrovascular diseases or other conditions that may lead to arterial hypotension. Quetiapine may cause orthostatic hypotension, especially at the beginning of dose titration, so dose reduction or more prolonged titration may be necessary in such cases. Interactions See also section "Interaction with other medicinal products and other types of interactions". Concomitant use of quetiapine with a potent hepatic enzyme inducer such as carbamazepine or phenytoin significantly reduces quetiapine plasma concentration, which may impair the effectiveness of quetiapine therapy. Quetimac treatment in patients receiving a hepatic enzyme inducer may only be initiated if the physician considers the benefit of Quetimac use to outweigh the risks of discontinuing the hepatic enzyme inducer. It is important that any changes in the use of the inducer occur gradually. If necessary, it should be replaced with a non-inducer (e.g., sodium valproate). Effect on body weight Weight gain has been reported during quetiapine treatment, which should be monitored and clinically managed when using antipsychotic agents. Hyperglycemia Hyperglycemia, development or worsening of diabetes mellitus, sometimes associated with ketoacidosis or coma, rarely observed, including several fatal cases (see section "Adverse reactions"). In several cases, patients had increased body weight, which may be a risk factor. Appropriate clinical monitoring is recommended according to current guidelines for the use of antipsychotic agents. Patients treated with any antipsychotic agents, including quetiapine, require monitoring for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes mellitus should be regularly checked for worsening glucose control. Body weight should be continuously monitored. Lipids Increased levels of triglycerides, low-density lipoproteins (LDL), and total cholesterol and decreased levels of high-density lipoprotein cholesterol (HDL) were observed in clinical trials of quetiapine (see section "Adverse reactions"). Appropriate treatment should be prescribed if lipid levels change. QT interval prolongation In clinical trials and during use according to instructions for medical use, quetiapine did not cause sustained increases in absolute QT intervals. However, QT interval prolongation was observed in cases of overdose. As with other antipsychotics, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases and patients with prolonged QT interval in family history. Caution should also be exercised when prescribing quetiapine with other drugs that prolong the QT interval or with neuroleptics, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, hypertrophy of the heart, hypokalemia, or hypomagnesemia (see section "Interaction with other medicinal products"). Severe skin adverse reactions Very rare reports of severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms, which may be life-threatening or fatal, have been reported during quetiapine treatment. Severe skin adverse reactions, which usually present as a combination of symptoms: extensive skin rash or exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia. If signs and symptoms indicating these severe skin reactions occur, quetiapine should be immediately discontinued and alternative treatment considered. Discontinuation of the drug Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability have been described after abrupt discontinuation of quetiapine. Therefore, a gradual discontinuation of the drug over a period of at least one to two weeks is recommended (see section "Adverse reactions"). Elderly patients with psychosis associated with dementia Quetimac is not recommended for the treatment of psychosis associated with dementia. In randomized placebo-controlled trials in dementia patients, use of some atypical antipsychotics was associated with an approximately 3-fold increase in the risk of cardiovascular adverse events. The mechanism of this increased risk is unknown. An increased risk cannot be excluded with the use of other antipsychotics or for other patient categories. Quetimac should be used with caution in patients with risk factors for stroke. Meta-analysis data of atypical antipsychotics show that elderly patients suffering from psychosis associated with dementia have an increased risk of fatal outcome compared to placebo. However, data from two 10-week placebo-controlled studies of quetiapine in elderly patients with dementia did not establish a causal relationship between quetiapine treatment and fatal outcome. Elderly patients with Parkinson's disease (PD)/parkinsonism Population retrospective analysis of quetiapine use for the treatment of patients with PD showed an increased risk of death during quetiapine use in patients over 65 years of age. These data were not confirmed when data from patients with Parkinson's disease were not included in the analysis results. Caution should be exercised if quetiapine is prescribed to elderly patients with PD. Dysphagia Dysphagia has been reported with quetiapine use. Quetiapine should be used with caution in patients at risk of aspiration pneumonia. Constipation and intestinal obstruction Constipation is a risk factor for the development of intestinal obstruction. Cases of constipation and intestinal obstruction have been reported with quetiapine use (see section "Adverse reactions"), including fatal cases in patients who had a higher risk of developing intestinal obstruction, including those receiving multiple drugs that reduce intestinal motility and/or drugs for which constipation may not have been reported. Venous thromboembolism Cases of venous thromboembolism (VTE) have been reported with the use of neuroleptic agents. Since patients taking neuroleptics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during quetiapine therapy and preventive measures taken. Effect on the liver Quetimac treatment should be discontinued if jaundice develops. Pancreatitis Cases of pancreatitis have been reported during clinical trials and post-marketing use, but a causal relationship has not been established. In post-marketing use reports, many patients had risk factors for pancreatitis such as elevated triglyceride levels (see section "Special precautions for use. Lipids"), gallstones, and alcohol consumption. Cardiomyopathy and myocarditis Cases of cardiomyopathy and myocarditis have been reported during clinical trials and the post-marketing period. Discontinuation of quetiapine should be considered in patients suspected of cardiomyopathy or myocarditis. 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 sections "Adverse reactions" and "Pharmacological properties"). An additive effect was observed in the third week of treatment. Lactose Quetimac tablets contain lactose. This medicinal product should not be used in patients with rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption. Quetimac 25/Quetimac 25 contains 5.175 mg of lactose monohydrate per tablet. Quetimac 100/Quetimac 100 contains 20.70 mg of lactose monohydrate per tablet. Quetimac 200/Quetimac 200 contains 41.40 mg of lactose monohydrate per tablet. 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 or substance abuse. Use during pregnancy or breastfeeding. Pregnancy First trimester A moderate amount of published data on pregnancy exposed to the drug (i.e., 300–1000 pregnancy cases), including individual reports and data from some observational studies, does not indicate an increased risk of developmental defects due to treatment. However, based on all available data, a definitive conclusion cannot be made. Animal studies have shown reproductive toxicity. Therefore, quetiapine should be used during pregnancy only if the expected benefit justifies the potential risks. Third trimester Newborns whose mothers took antipsychotic drugs (including quetiapine) in the third trimester have a risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration after birth. Adverse reactions observed include agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory disorders, or feeding disorders. Therefore, newborns should be under close supervision. Breastfeeding There are reports that quetiapine passes into human breast milk, although the extent of drug penetration into milk is unknown. Due to the lack of reliable data in breastfeeding women, a decision should be made to discontinue breastfeeding during quetiapine treatment or to discontinue treatment during breastfeeding, 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. Effects related to increased prolactin levels were observed in rats, although they are not directly relevant to humans. Ability to affect reaction speed when driving or operating machinery. Since quetiapine primarily affects the central nervous system, patients should not drive or operate machinery until their individual sensitivity to such effects is determined. Method of administration and dosage. Different dosing regimens are prescribed for each indication. Ensure that the prescribed dosage corresponds to the patient's condition. Quetimac can be taken with or without food. Adults For the treatment of schizophrenia For the treatment of schizophrenia, Quetimac should be administered twice daily. The total daily dose during the first four days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), and 300 mg (day 4). From day 4, the dose should be gradually adjusted to the usual effective dose of 300–450 mg per day. Depending on the individual patient's clinical response and tolerability, the dose can be adjusted within the range of 150–750 mg per day. For the treatment of moderate and severe manic episodes in bipolar disorder. For the treatment of manic episodes associated with bipolar disorder, Quetimac should be taken twice daily. The total daily dose during the first four days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3), and 400 mg (day 4). Further dose adjustment up to 800 mg per day by day 6 should be in increments of no more than 200 mg per day. The dose can be adjusted depending on the individual patient's clinical response and tolerability within the range of 200–800 mg per day. The usual effective dose is 400–800 mg per day. For the treatment of major depressive episodes in bipolar disorder Quetimac should be taken once daily before bedtime. The total daily dose during the first four days of therapy 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. In clinical trials, no additional benefit was observed in the 600 mg group compared to the 300 mg group. A dose of 600 mg may be beneficial for individual patients. Doses exceeding 300 mg should be initiated by physicians experienced in treating bipolar disorder. In individual patients, if tolerance is a concern, clinical trials have shown that dose reduction to a minimum of 200 mg may be considered. For the prevention of relapses in bipolar disorder For the prevention of relapses of manic, mixed, or depressive episodes in bipolar disorder in patients who have responded to quetiapine for acute treatment of bipolar disorder, therapy should be continued at the same dose. The dose can be adjusted depending on the individual patient's clinical response and tolerability within the range of 300–800 mg per day, administered twice daily. It is important that the lowest effective dose be used for maintenance therapy. Elderly patients As with other antipsychotic agents, Quetimac should be used with caution in elderly individuals, especially during the initial dosing period. The rate of dose titration may be slower, and the daily therapeutic dose lower than in younger patients, depending on the individual patient's clinical response and tolerability. The average plasma clearance of quetiapine in elderly patients was reduced by 30–50% 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 actively metabolized by the liver. Therefore, Quetimac should be used with caution in patients with known liver function impairment, especially during the initial dosing period. Patients with known liver function impairment should start with 25 mg/day. The dose should be increased daily by 25–50 mg/day until an effective dose is reached depending on the individual patient's clinical response and tolerability. Children Quetimac is not recommended for use in children and adolescents under 18 years of age due to lack of data confirming use in this age group. Overdose. During clinical trials, survival has been reported in acute overdoses of up to 30 g of quetiapine. Most patients with overdose did not report adverse events or fully recovered from such events. A fatal outcome was reported during a clinical trial after an overdose of 13.6 g of quetiapine. During post-marketing use, reports of quetiapine overdose leading to fatal outcome, coma, or QT interval prolongation were very rare. Symptoms The following events were recorded under conditions of monotherapy overdose of quetiapine: QT interval prolongation, seizures, epileptic status, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium, and/or agitation. Patients with severe cardiovascular disease have an increased risk of overdose effects (see section "Special precautions for use"). In general, the symptoms reported were consequences of the enhanced known pharmacological effects of the drug, such as somnolence and sedation, tachycardia, and arterial hypotension. Treatment There is no specific antidote for quetiapine. In cases of severe complications, necessary measures and intensive therapy should be considered, including restoration and maintenance of airway patency, ensuring adequate oxygenation and ventilation, monitoring and support of cardiovascular function. Cases of resolution of serious CNS reactions, including coma and delirium, have been described. Patients with delirium and agitation, as well as clear manifestations of anticholinergic syndrome, may be treated with physostigmine at a dose of 1–2 mg (intravenous administration under continuous ECG monitoring). This is not a recommendation for standard treatment due to the possible negative effect of physostigmine on cardiac conduction. Physostigmine may be used in the absence of ECG disturbances. Physostigmine should not be used in cases of rhythm disturbances, any degree of block, or QRS complex widening. In cases of persistent arterial hypotension in quetiapine overdose, appropriate measures such as intravenous fluid administration and/or sympathomimetics should be applied (adrenaline and dopamine should be avoided as stimulation of beta-adrenergic receptors may exacerbate hypotension under conditions of alpha-adrenergic receptor blockade caused by quetiapine). Since prevention of absorption in overdose has not been studied, the necessity of gastric lavage (after intubation if the patient is unconscious) and the use of activated charcoal with a laxative should be considered. Close medical supervision and monitoring should continue until full recovery of the patient. Adverse reactions. The most frequently reported adverse reactions during quetiapine administration are: somnolence, dizziness, dry mouth, headache, withdrawal symptoms (discontinuation of use), increased serum triglyceride levels, increased total cholesterol levels (especially LDL cholesterol), decreased HDL cholesterol levels, weight gain, decreased hemoglobin levels, and extrapyramidal symptoms. As with the use of other antipsychotic agents, quetiapine use was associated with weight gain, syncope, neuroleptic malignant syndrome, leukopenia, and peripheral edema. The frequency of adverse events during quetiapine treatment is listed below according to the following classification: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data).

1. See section "Special instructions".
2. Drowsiness may occur, usually within the first 2 weeks of treatment, and typically resolves with continued use of quetiapine.
3. Asymptomatic elevations (deviations from normal up to > 3 × ULN [upper limit of normal] at any time) in transaminase levels (ALT, AST) or gamma-GT (glutamyl transferase) have been observed in some patients during quetiapine treatment. These elevations were usually reversible with continued quetiapine therapy.
4. Like other antipsychotic medicinal products blocking alpha1-adrenergic receptors, quetiapine frequently may cause orthostatic hypotension, accompanied by dizziness, tachycardia, and in some patients, syncope, particularly during the initial dose titration period (see section "Special instructions").
5. Rarely, worsening of pre-existing diabetes mellitus has been reported.
6. The frequency of these adverse reactions was assessed only based on post-marketing data from the use of quetiapine in the immediate-release formulation.
7. Fasting blood glucose level ≥ 126 mg/dL (≥ 7.0 mmol/L) or postprandial blood glucose level ≥ 200 mg/dL (≥ 11.1 mmol/L) at least once.
8. Increased incidence of dysphagia with quetiapine compared to placebo was observed only in clinical trials of bipolar depression.

9. 7% increase in body weight compared to baseline. Occurs predominantly during the first weeks of therapy in adults.

10. Withdrawal symptoms most commonly observed in short-term placebo-controlled monotherapy clinical trials: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions substantially decreased within one week after discontinuation of treatment.
11. Triglyceride level ≥ 200 mg/dL (≥ 2.258 mmol/L) (patients aged ≥ 18 years) or ≥ 150 mg/dL (≥ 1.694 mmol/L) (patients aged < 18 years) at least once.
12. Cholesterol level ≥ 240 mg/dL (≥ 6.2064 mmol/L) (patients aged ≥ 18 years) or ≥ 200 mg/dL (≥ 5.172 mmol/L) (patients aged < 18 years) at least once. Increase in LDL-cholesterol level ≥ 30 mg/dL (≥ 0.769 mmol/L) was observed very commonly. The mean value in patients with such an increase in LDL-cholesterol was 41.7 mg/dL (1.07 mmol/L).
13. Platelet count ≤ 100 × 10⁹/L at least once.
14. Platelets ≤ 100 × 10⁹/L at least once.
15. According to clinical trial data on adverse reactions, elevated blood creatine phosphokinase levels were not associated with neuroleptic malignant syndrome.
16. Prolactin level (patients aged > 18 years) > 20 µg/L (> 869.56 pmol/L) in males; > 30 µg/L (> 1304.34 pmol/L) in females at any time.
17. May lead to falls.
18. HDL-cholesterol < 40 mg/dL (1.025 mmol/L) in males; < 50 mg/dL (1.282 mmol/L) in females at any time.
19. Number of patients in whom QTc interval duration changed from < 450 ms to ≥ 450 ms with an increase of ≥ 30 ms. In placebo-controlled quetiapine studies, mean changes and the number of patients with deviations to clinically significant levels were similar in quetiapine and placebo groups.
20. Deviation from > 132 mmol/L to ≤ 132 mmol/L in at least one examination.
21. Cases of suicidal thoughts and suicidal behavior have been reported during therapy with quetiapine or immediately after discontinuation of treatment (see sections "Special instructions" and "Pharmacological properties").
22. See section "Pharmacological properties".
23. Decrease in hemoglobin level to ≤ 13 g/dL (8.07 mmol/L) in males, ≤ 12 g/dL (7.45 mmol/L) in females at least once was observed in 11% of patients treated with quetiapine across all studies, including open-label studies. For these patients, the mean maximum decrease in hemoglobin level at any time was 1.50 g/dL.
24. Frequently observed in the context of tachycardia, dizziness, orthostatic hypotension, and/or underlying cardiac/respiratory disorders.
25. Deviation from normal baseline to potentially clinically significant values at any time after initiation of treatment in all studies. Deviations in total T4, free T4, total T3, and free T3 were < 0.8 × LNL (lower limit of normal) (pmol/L), and TSH deviation was > 5 mIU/L at any time.
26. Increased incidence of vomiting in elderly patients (≥ 65 years).
27. Deviation in neutrophil count from baseline ≥ 1.5 × 10⁹/L to < 0.5 × 10⁹/L at any time during treatment.
28. Deviation from normal baseline to potentially clinically significant values at any time after initiation of treatment in all studies. Eosinophil deviation was > 1 × 10⁹ cells/L at any time.
29. Deviation from normal baseline to potentially clinically significant values at any time after initiation of treatment in all studies. Leukocyte deviation was ≤ 3 × 10⁹ cells/L at any time.
30. According to reports of adverse reactions related to metabolic syndrome from all clinical trials of quetiapine.
31. In clinical trials, some patients experienced more than one increase in metabolic factors negatively affecting body weight, blood glucose, and lipids (see section "Special instructions").
32. See section "Use in pregnancy or lactation".
33. May occur during or shortly after initiation of therapy and may be associated with hypotension and/or syncope. The incidence is based on reports of bradycardia and related events observed in all clinical trials of quetiapine.

Cases of prolonged QT interval, ventricular arrhythmia, sudden unexplained death, cardiac arrest, and torsade de pointes-type arrhythmia have been reported with the use of neuroleptic medicinal products and are considered class-specific. Shelf life: 3 years. Storage conditions: Store at temperatures not exceeding 30 °C, in the original packaging. Keep out of reach of children. Packaging: 10 tablets per blister, 3 or 6 blisters per cardboard pack. Prescription status: Prescription only. Manufacturer: MACLEODS PHARMACEUTICALS LIMITED. Manufacturer's address and location of operations: Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.