Quetiapine Canon 25 mg 60 coated tablets

The drug Quetiapine Canon is indicated for use in adults aged 18 years and older for the treatment of:
- schizophrenia;
- manic episodes in the context of bipolar disorder;
- depressive episodes of moderate to severe severity in the context of bipolar disorder.
The drug is not indicated for the prevention of manic and depressive episodes.

Orally, regardless of food intake.
Treatment of schizophrenia
Quetiapine Canon is prescribed twice daily.
The daily dose for the first 4 days of therapy 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 adjusted to an effective level, usually between 300 to 450 mg/day. Depending on the clinical effect and individual tolerance, the dose may vary between 150 to 750 mg/day.
The maximum recommended dose of Quetiapine Canon is 750 mg/day.
Treatment of manic episodes in bipolar disorder
Quetiapine Canon is recommended as monotherapy or as adjunctive therapy for mood stabilization.
The medication is prescribed twice daily.
The daily dose for the first 4 days of therapy is: Day 1 - 100 mg, Day 2 - 200 mg, Day 3 - 300 mg, Day 4 - 400 mg. Subsequently, by Day 6 of therapy, the daily dose may be increased to 800 mg. The increase in daily dose should not exceed 200 mg per day. Depending on the clinical effect and individual tolerance, the dose may vary between 200 to 800 mg/day. The effective dose is usually between 400 to 800 mg/day.
The maximum recommended dose of Quetiapine Canon is 800 mg/day.
Treatment of depressive episodes in bipolar disorder
Quetiapine Canon is prescribed once daily at night.
The daily dose for the first 4 days of therapy is: Day 1 - 50 mg, Day 2 - 100 mg, Day 3 - 200 mg, Day 4 - 300 mg. The recommended dose is 300 mg/day.
The maximum recommended dose of Quetiapine Canon is 600 mg/day.
The antidepressant effect of quetiapine has been confirmed at daily doses of 300 mg and 600 mg. In short-term therapy, the efficacy of quetiapine at doses of 300 mg/day and 600 mg/day was comparable.
Elderly patients
Quetiapine Canon should be prescribed to elderly patients with caution, especially during the initial dose adjustment, starting with a dose of 25 mg/day, with subsequent daily increases of 25-50 mg until an effective dose is reached, which is likely to be lower than that for younger patients. If necessary, the dose of quetiapine can be titrated more slowly, taking into account therapeutic efficacy and individual tolerance.
Patients with renal impairment
Dose adjustment is not required.
Patients with hepatic impairment
Quetiapine Canon is extensively metabolized in the liver. Therefore, caution should be exercised when using Quetiapine Canon in patients with liver insufficiency, especially at the beginning of therapy. It is recommended to start therapy with a dose of 25 mg/day and increase the dose daily by 25-50 mg until an effective dose is reached.

1 film-coated tablet contains:
Active ingredient: quetiapine fumarate (quetiapine hemifumarate) 28.78 mg, calculated as quetiapine 25.00 mg.
Excipients: hypromellose (hydroxypropyl cellulose Klucel LF) 3.20 mg, calcium hydrogen phosphate dihydrate 45.79 mg, calcium stearate 1.23 mg, pregelatinized corn starch 6.00 mg, magnesium stearate 1.00 mg, sodium carboxymethyl starch 2.00 mg, microcrystalline cellulose (type 101) 32.00 mg.
Coating composition: AquaPolish® D blue 3.00 mg, including [hydroxypropyl methylcellulose 1.50 mg, glycerol (glycerin) 0.15 mg, microcrystalline cellulose 0.30 mg, talc 0.44 mg, colorant candurin silver sheen 0.54 mg, colorant indigo carmine 0.07 mg]

Tablets are round, biconvex, coated with a blue film with a pearlescent sheen. In cross-section, the core is almost white in color.

-Hypersensitivity to any component of the drug.
-Concurrent use with cytochrome P450 inhibitors, such as azole antifungals, erythromycin, clarithromycin, and nefazodone, as well as with human immunodeficiency virus (HIV) protease inhibitors (see the section "Interactions with Other Medicinal Products").
-Breastfeeding period.
-Children under 18 years of age (efficacy and safety not established).

With caution:
In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; elderly patients, those with liver insufficiency; a history of seizures, risk of stroke, and aspiration pneumonia.

Children and adolescents (aged 10 to 17 years)
The drug Quetiapine Canon is not indicated for use in children and adolescents under 18 years of age due to insufficient data on its use in this age group.
According to clinical trial results, some adverse reactions (increased appetite, increased serum prolactin levels, vomiting, runny nose, and fainting) were observed more frequently in children and adolescents than in adult patients. Some adverse reactions (extrapyramidal symptoms) in children and adolescents may have different consequences compared to adult patients. An increase in blood pressure was also noted, which was not observed in adult patients. Changes in thyroid function were also observed in children and adolescents.
The effects on growth, sexual maturation, mental development, and behavioral responses with prolonged use (more than 26 weeks) of quetiapine have not been studied.
In placebo-controlled studies in children and adolescents with schizophrenia and mania in the context of bipolar disorder, the incidence of extrapyramidal symptoms was higher with quetiapine compared to placebo.
Suicide/suicidal thoughts or clinical deterioration
Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal events). This risk persists until significant remission occurs. Since it may take several weeks or longer for a patient’s condition to improve from the start of treatment, patients should be closely monitored until improvement occurs.
According to general clinical experience, the risk of suicide may increase in the early stages of remission. Patients (especially those in high-risk groups for suicide) and their caregivers should be warned about the need to monitor for clinical deterioration, suicidal behavior or thoughts, unusual changes in behavior, and the necessity to contact a physician immediately if they occur.
In clinical studies of patients with depression in bipolar disorder, the risk of suicidal events was 3.0% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18-24 years; 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo, respectively, in patients over 25 years.
Other mental disorders for which quetiapine is prescribed are also associated with an increased risk of suicidal events. Additionally, such conditions may be comorbid with depressive episodes. Therefore, precautions taken when treating patients with depressive episodes should also be applied when treating patients with other mental disorders.
In the event of abrupt discontinuation of quetiapine therapy, the potential risk of developing suicidal events should be considered.
Patients with a history of suicidal events, as well as patients who express suicidal thoughts prior to the start of therapy, are at high risk for suicidal intentions and attempts and should be closely monitored during treatment. A meta-analysis conducted by the FDA (U.S. Food and Drug Administration) of placebo-controlled studies of antidepressants, summarizing data from approximately 4,400 children and adolescents and 7,700 adult patients with mental disorders, revealed an increased risk of suicidal behavior associated with antidepressants compared to placebo in children, adolescents, and adult patients under 25 years of age. This meta-analysis does not include studies where quetiapine was used (see the section "Pharmacological properties. Pharmacodynamics").
According to short-term placebo-controlled studies across all indications and age groups, the incidence of suicidal events was 0.8% for both quetiapine (76/9327) and placebo (37/4845).
In these studies, the risk of developing suicidal events in patients with schizophrenia was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients aged 18-24 years; 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients over 25 years; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under 18 years.
In patients with mania in bipolar disorder, the risk of developing suicidal events was 0% (0/60) for quetiapine and 0% (0/58) for placebo in patients aged 18-24 years; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients over 25 years; 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients under 18 years.
Drowsiness
During therapy with Quetiapine Canon, drowsiness and related symptoms, such as sedation, may be observed (see the section "Adverse reactions"). In clinical studies involving patients with depression in the context of bipolar disorder, drowsiness typically developed within the first three days of therapy. The severity of this adverse reaction was generally mild to moderate. If significant drowsiness occurs, patients with depression in the context of bipolar disorder may require more frequent visits to the physician within 2 weeks from the onset of drowsiness or until the severity of symptoms decreases. In some cases, discontinuation of Quetiapine Canon therapy may be necessary.
Patients with cardiovascular diseases
Caution should be exercised when prescribing quetiapine to patients with cardiovascular and cerebrovascular diseases and other conditions predisposing to arterial hypotension. Orthostatic hypotension may occur during quetiapine therapy, especially during dose titration at the beginning of treatment. Orthostatic hypotension and associated dizziness may increase the risk of accidental injury (falls), particularly in elderly patients. Patients should be cautious until they adapt to these potential adverse reactions. If orthostatic hypotension occurs, dose reduction or slower titration may be necessary.
Sleep apnea syndrome
Sleep apnea syndrome has been noted in patients taking quetiapine. Caution should be exercised when prescribing quetiapine to patients receiving central nervous system depressants, as well as to patients with risk factors for sleep apnea (e.g., overweight/obesity, male gender) or with a history of sleep apnea.
Seizures
No differences in the incidence of seizures were found in patients taking quetiapine or placebo. However, as with therapy with other antipsychotic medications, caution is recommended when treating patients with a history of seizures (see the section "Adverse reactions").
Extrapyramidal symptoms
An increased incidence of extrapyramidal symptoms has been noted in patients with depression in the context of bipolar disorder when taking quetiapine for depressive episodes compared to placebo (see the section "Adverse reactions").
Akatisia may occur during quetiapine treatment, characterized by an unpleasant feeling of motor restlessness, a need to move, and an inability of the patient to sit or stand still. If such symptoms occur, the dose of quetiapine should not be increased.
Tardive dyskinesia
If symptoms of tardive dyskinesia develop, it is recommended to reduce the dose of the drug or gradually discontinue it. Symptoms of tardive dyskinesia may worsen or even arise after discontinuation of the drug (see the section "Adverse reactions").
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome may develop during the use of antipsychotic medications, including quetiapine (see the section "Adverse reactions"). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system lability, and increased plasma CPK activity. In such cases, quetiapine should be discontinued, and appropriate treatment should be initiated.
Severe neutropenia and agranulocytosis
In short-term placebo-controlled clinical studies of quetiapine monotherapy, cases of severe neutropenia (neutrophil count < 0.5 x 10^9/L) without infection were infrequently reported. Agranulocytosis (severe neutropenia associated with infections) has been reported in patients receiving quetiapine in clinical studies (rarely), as well as in post-marketing use (including with fatal outcomes). Most of these cases of severe neutropenia occurred several months after the initiation of quetiapine therapy. No dose-dependent effect was identified. Leukopenia and/or neutropenia resolved after discontinuation of quetiapine therapy. Possible risk factors for the development of neutropenia include a prior low white blood cell count and a history of drug-induced neutropenia. Agranulocytosis has also been noted in patients without risk factors. The possibility of developing neutropenia in patients with infection should be considered, especially in the absence of obvious predisposing factors, or in patients with unexplained fever; these cases should be managed according to clinical guidelines. In patients with neutrophil counts < 1.0 x 10^9/L, quetiapine should be discontinued. The patient should be monitored for possible symptoms of infection and neutrophil counts should be controlled (until exceeding 1.5 x 10^9/L). Interaction with other medications See also the section "Interaction with other medications." The use of quetiapine in combination with potent inducers of hepatic microsomal enzymes, such as carbamazepine and phenytoin, contributes to a decrease in quetiapine plasma concentration and may reduce the effectiveness of Quetiapine Canon therapy. The use of Quetiapine Canon in patients receiving inducers of hepatic microsomal enzymes is only possible if the expected benefit of therapy with Quetiapine Canon outweighs the risk associated with the discontinuation of the inducers of hepatic microsomal enzymes. Changes in the dose of inducers of hepatic microsomal enzymes should be gradual. If necessary, they may be replaced with medications that do not induce hepatic microsomal enzymes (e.g., valproic acid medications). Hyperglycemia Hyperglycemia or exacerbation of diabetes mellitus (in some cases leading to ketoacidosis or coma, including with fatal outcomes) may develop in patients with a history of diabetes mellitus during quetiapine therapy. Monitoring of patients receiving quetiapine and other neuroleptics for possible symptoms of hyperglycemia, such as polyuria (increased urine output), polydipsia (pathologically increased thirst), polyphagia (increased appetite), and weakness, is recommended. Monitoring of patients with diabetes mellitus and patients with risk factors for developing diabetes mellitus for possible deterioration in glycemic control is also recommended (see the section "Adverse reactions"). Regular monitoring of body weight is advised. Lipid concentration An increase in triglycerides, cholesterol, and LDL levels, as well as a decrease in HDL levels in plasma, may occur during quetiapine therapy (see the section "Adverse reactions"). Metabolic disorders Weight gain, increased glucose and lipid levels in plasma in some patients may lead to deterioration of the metabolic profile, requiring appropriate monitoring. QT interval prolongation No relationship has been found between quetiapine use and a persistent increase in the absolute QT interval. However, QT interval prolongation has been noted in cases of overdose (see the section "Overdose"). Caution should be exercised when prescribing quetiapine, as well as other antipsychotic medications, to patients with cardiovascular diseases and previously noted QT interval prolongation. Caution is also necessary when prescribing quetiapine simultaneously with medications that prolong the QT interval, other neuroleptics, especially in elderly individuals, in patients with congenital long QT syndrome, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see the section "Interaction with other medications"). Cardiomyopathy and myocarditis Cases of cardiomyopathy and myocarditis have been noted during clinical studies and post-marketing use; however, a causal relationship with the drug has not been established. The appropriateness of quetiapine therapy in patients suspected of having cardiomyopathy or myocarditis should be evaluated. Severe skin adverse reactions Severe skin adverse reactions have been reported during quetiapine use, including Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which are potentially life-threatening adverse drug reactions. Severe skin adverse reactions typically manifest with one or more of the following symptoms: extensive rash that may be itchy or accompanied by pustules, exfoliative dermatitis, fever, lymphadenopathy, and potential eosinophilia or neutrophilia. If severe skin adverse reactions occur, quetiapine should be discontinued. Acute reactions due to drug withdrawal Abrupt discontinuation of quetiapine may result in the following acute reactions (withdrawal syndrome): nausea, vomiting, insomnia, headache, dizziness, and irritability. Therefore, discontinuation of the drug is recommended to be gradual over at least one or two weeks. Misuse and abuse of the drug Cases of misuse and abuse of quetiapine have been reported. Caution should be exercised when prescribing quetiapine to patients with a history of alcohol or drug abuse. Elderly patients with dementia Quetiapine Canon is not indicated for the treatment of psychosis associated with dementia. Some atypical antipsychotics in randomized placebo-controlled studies have approximately tripled the risk of cerebrovascular complications in patients with dementia. The mechanism of this increased risk has not been studied. A similar risk of increased frequency of cerebrovascular complications cannot be excluded for other antipsychotic medications or other patient groups. Quetiapine Canon should be used with caution in patients at risk of stroke. An analysis of the use of atypical antipsychotics for the treatment of psychosis associated with dementia in elderly patients revealed an increased mortality rate in the group of patients receiving these medications compared to the placebo group. Additionally, two 10-week placebo-controlled studies of quetiapine in a similar group of patients (n = 710; mean age: 83 years; age range: 56-99 years) showed that the mortality rate in the group of patients taking quetiapine was 5.5% and 3.2% in the placebo group. The causes of death noted in these patients were consistent with those expected for this population. No causal relationship between quetiapine treatment and the risk of increased mortality in elderly patients with dementia was established. Anticholinergic (muscarinic-like) effects Norquetiapine, the active metabolite of quetiapine, has affinity (ranging from moderate to strong) for several subtypes of muscarinic receptors. This is associated with adverse reactions caused by the anticholinergic effect of quetiapine when used at recommended doses or in combination with other medications that have anticholinergic effects, as well as in cases of overdose. Caution should be exercised when using quetiapine in conjunction with medications that have anticholinergic (muscarinic-like) effects. Caution should be exercised when prescribing quetiapine to patients with urinary retention or a history of urinary retention, clinically significant benign prostatic hyperplasia, intestinal obstruction or related conditions, increased intraocular pressure, or angle-closure glaucoma (see the sections "Pharmacological properties. Pharmacodynamics," "Adverse reactions," "Overdose," "Interaction with other medications"). Liver disorders If jaundice develops, the use of Quetiapine Canon should be discontinued. Dysphagia Dysphagia (see the section "Adverse reactions") and aspiration have been observed during quetiapine therapy. A causal relationship between the occurrence of aspiration pneumonia and quetiapine use has not been established. However, caution should be exercised when prescribing Quetiapine Canon to patients at risk of aspiration pneumonia. Venous thromboembolism Cases of venous thromboembolism have been noted during the use of neuroleptics. Since patients taking neuroleptics often have risk factors for venous thromboembolism, risk factors should be assessed and preventive measures taken before and during therapy with antipsychotic medications, including quetiapine. Constipation and intestinal obstruction Constipation is a risk factor for intestinal obstruction. Cases of constipation and intestinal obstruction (see the section "Adverse reactions") have been reported during quetiapine use, including cases with fatal outcomes in high-risk patients for intestinal obstruction, including those receiving multiple concomitant medications that reduce intestinal motility, even in the absence of complaints of constipation. Pancreatitis Cases of pancreatitis have been noted during clinical studies and post-marketing use; however, a causal relationship with the drug has not been established. Post-marketing reports indicate that many patients had risk factors for developing pancreatitis, such as increased triglyceride levels (see the subsection "Lipid concentration"), cholelithiasis, and alcohol use. Additional information Data on the simultaneous use of quetiapine with divalproex or lithium in acute manic episodes of mild or moderate severity are limited. Good tolerability of this combination therapy and an additive effect by the third week of therapy have been noted. Special information about excipients Quetiapine Canon contains glycerol (glycerin), which may cause headache, stomach upset, and diarrhea.

Most common side effects of quetiapine (≥ 10%) - drowsiness, dizziness, dry mouth, withdrawal syndrome, increased triglyceride levels, increased total cholesterol levels (mainly low-density lipoprotein cholesterol - LDL), decreased high-density lipoprotein cholesterol (HDL), weight gain, decreased hemoglobin levels, and extrapyramidal symptoms (EPS).

The frequency of side effects is presented in the following gradation: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated based on available data).Organ system class | Adverse reaction ---------------------|------------------- Blood and lymphatic system disorders | common leukopenia1, 25; frequency unknown neutropenia1 Immune system disorders | uncommon hypersensitivity reactions; very rare anaphylactic reactions6 Metabolism and nutrition disorders | very rare diabetes mellitus1,5,6 Nervous system disorders | very common dizziness1,4,17, headache, drowsiness2,17, EPS1,13; common dysarthria, unusual and nightmare dreams, increased appetite; uncommon seizures1, restless legs syndrome, tardive dyskinesia1, fainting1,4,17, confusion; rare sleepwalking and related phenomena Eye disorders | common blurred vision Cardiac disorders | common tachycardia1,4, palpitations19; uncommon bradycardia26; frequency unknown cardiomyopathy and myocarditis Vascular disorders | common orthostatic hypotension1,4, 17 Respiratory system, thoracic organs, and mediastinal disorders | common dyspnea19; uncommon rhinitis Gastrointestinal disorders | very common dry mouth; common dyspepsia, constipation, vomiting21; uncommon dysphagia1,8; rare intestinal obstruction/ileus Liver and biliary tract disorders | rare jaundice6; very rare hepatitis (with or without jaundice)6 Skin and subcutaneous tissue disorders | very rare angioedema6, Stevens-Johnson syndrome6; frequency unknown toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), cutaneous vasculitis Musculoskeletal and connective tissue disorders | very rare rhabdomyolysis Kidney and urinary tract disorders | uncommon urinary retention Pregnancy, postpartum, and perinatal conditions | frequency unknown withdrawal syndrome in newborns28 Reproductive system and breast disorders | rare priapism, galactorrhea General disorders and administration site conditions | very common withdrawal syndrome1,10; common mild asthenia, peripheral edema, irritability, fever; rare malignant neuroleptic syndrome1, hypothermia Laboratory and instrumental data | very common increased triglyceride levels1,11, total cholesterol (mainly LDL cholesterol)1,12, decreased HDL cholesterol1,18, weight gain9, decreased hemoglobin levels23; common increased alanine aminotransferase (ALT)3, increased gamma-glutamyltransferase (GGT)3, decreased neutrophil count1,22, increased eosinophil count24, hyperglycemia1,7, hyperprolactinemia16, decreased total and free thyroxine (T4)20, decreased total triiodothyronine (T3)20, increased thyroid-stimulating hormone (TSH)20; uncommon thrombocytopenia14, increased aspartate aminotransferase (AST)3, prolonged QT interval1,13, decreased free T320; rare increased creatine phosphokinase (CPK)15, agranulocytosis271. See "Special Instructions" section. 2. Drowsiness usually occurs within the first 2 weeks after starting therapy and typically resolves with continued quetiapine use. 3. Asymptomatic increases (≥ 3 times the upper limit of normal when measured at any time) in AST, ALT, and GGT activity in serum are generally reversible with continued quetiapine use. 4. Like other antipsychotic drugs with α1-adrenergic blocking action, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia, and in some cases fainting, especially at the beginning of therapy (see "Special Instructions" section). 5. Very rare cases of exacerbation of diabetes mellitus have been reported. 6. The frequency of this side effect was assessed based on post-marketing surveillance results. 7. Fasting plasma glucose levels ≥ 126 mg/dL (≥ 7.0 mmol/L) or postprandial plasma glucose levels ≥ 200 mg/dL (≥ 11.1 mmol/L) at least once. 8. A higher frequency of dysphagia with quetiapine compared to placebo was noted only in patients with depression in the context of bipolar disorder. 9. An increase in baseline body weight of 7% or more. Primarily occurs at the beginning of therapy in adults. 10. In studies of withdrawal syndrome in short-term placebo-controlled clinical trials of quetiapine in monotherapy, the following symptoms were noted: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of withdrawal syndrome significantly decreased after 1 week following discontinuation of the drug. 11. An increase in triglyceride levels ≥ 200 mg/dL (≥ 2.258 mmol/L) in patients ≥ 18 years or ≥ 150 mg/dL (≥ 1.694 mmol/L) in patients < 18 years, at least once. 12. An increase in total cholesterol levels ≥ 240 mg/dL (≥ 6.2064 mmol/L) in patients ≥ 18 years or ≥ 200 mg/dL (≥ 5.172 mmol/L) in patients 20 μg/L (≥ 869.56 pmol/L) in men; > 30 μg/L (≥ 1304.34 pmol/L) in women.
17. May lead to falls.
18. A decrease in HDL cholesterol levels < 40 mg/dL (< 1.03 mmol/L) in men and < 50 mg/dL (< 1.29 mmol/L) in women. 19. These side effects were often noted against the background of tachycardia, dizziness, orthostatic hypotension, and/or concomitant cardiovascular or respiratory pathology. 20. Based on potentially clinically significant deviations from normal baseline levels noted in all clinical studies. Changes in total T4, free T4, total T3, free T3 concentrations to values 5 mIU/L when measured at any time.
21. Based on the increased frequency of vomiting in elderly patients (≥ 65 years).
22. In short-term clinical studies of quetiapine monotherapy in patients with neutrophil counts ≥ 1.5 x 10^9/L before therapy, cases of neutropenia (neutrophil count < 1.5 x 10^9/L) were noted in 1.9% of patients in the quetiapine group compared to 1.5% in the placebo group. A decrease in neutrophil count ≥ 0.5 but < 1.0 x 10^9/L was noted with a frequency of 0.2% in both the quetiapine and placebo groups. A decrease in neutrophil count < 0.5 x 10^9/L at least once was noted in 0.21% of patients in the quetiapine group compared to 0% in the placebo group. 23. A decrease in hemoglobin levels ≤ 13 g/dL in men and ≤ 12 g/dL in women, at least once was noted in 11% of patients on quetiapine in all clinical studies, including long-term therapy. In short-term placebo-controlled studies, a decrease in hemoglobin levels ≤ 13 g/dL in men and ≤ 12 g/dL in women, at least once, was noted in 8.3% of patients in the quetiapine group compared to 6.2% in the placebo group. 24. Based on potentially clinically significant deviations from baseline normal levels noted in all clinical studies. An increase in eosinophil count ≥ 1 x 10^9/L when measured at any time. 25. Based on potentially clinically significant deviations from baseline normal levels noted in all clinical studies. A decrease in leukocyte count ≤ 3 x 10^9/L when measured at any time. 26. May develop at the moment or soon after the start of therapy and be accompanied by hypotension and/or fainting. The frequency was established based on reports of bradycardia and related side effects in all clinical studies of quetiapine. 27. Based on the frequency assessment in patients who participated in all clinical studies of quetiapine, who had severe neutropenia (< 0.5 x 10^9/L) in combination with infections. 28. See "Use in Pregnancy and Breastfeeding" section.QT interval prolongation, ventricular arrhythmia, sudden death, cardiac arrest, and bidirectional ventricular tachycardia are considered side effects associated with neuroleptics.The frequency of EPS in short-term clinical studies in adult patients with schizophrenia and mania in the context of bipolar disorder was comparable in the quetiapine and placebo groups (patients with schizophrenia: 7.8% in the quetiapine group and 8.0% in the placebo group; mania in the context of bipolar disorder: 11.2% in the quetiapine group and 11.4% in the placebo group).The frequency of EPS in short-term clinical studies in adult patients with depression in the context of bipolar disorder in the quetiapine group was 8.9%, in the placebo group - 3.8%. At the same time, the frequency of individual EPS symptoms (such as akathisia, extrapyramidal disorders, tremor, dyskinesia, dystonia, anxiety, involuntary muscle contractions, psychomotor agitation, and muscle rigidity) was generally low and did not exceed 4% in each treatment group. In long-term clinical studies of quetiapine in schizophrenia and bipolar disorder in adult patients, the frequency of EPS was comparable in the quetiapine and placebo groups.During quetiapine therapy, a dose-dependent decrease in thyroid hormone levels may be noted. The frequency of potentially clinically significant changes in thyroid hormone levels in short-term clinical studies for total T4 was 3.4% in the quetiapine group and 0.6% in the placebo group; for free T4 - 0.7% in the quetiapine group versus 0.1% in the placebo group; for total T3 - 0.54% in the quetiapine group versus 0.0% in the placebo group; for free T3 - 0.2% in the quetiapine group versus 0.0% in the placebo group. Changes in TSH concentration were noted with a frequency of 3.2% in the quetiapine group and 2.7% in the placebo group.In short-term clinical studies of monotherapy, the frequency of potentially clinically significant changes in T3 and TSH concentrations was 0.0% in both the quetiapine and placebo groups; for T4 and TSH it was 0.1% in the quetiapine group versus 0.0% in the placebo group. These changes are generally not associated with clinically significant hypothyroidism. The maximum decrease in total and free T4 was recorded at week 6 of quetiapine therapy, with no further decrease in hormone levels during long-term treatment. In almost all cases, total and free T4 concentrations returned to baseline levels after discontinuation of quetiapine therapy, regardless of the duration of treatment. The concentration of thyroxine-binding globulin (TBG) remained unchanged in 8 patients.There have been reports of fatal outcomes following the ingestion of 13.6 g of quetiapine in a patient participating in a clinical trial, as well as a fatal outcome after taking 6 g of quetiapine during a post-marketing study of the drug. At the same time, a case has been described where quetiapine was taken in a dose exceeding 30 g without a fatal outcome.There are reports of extremely rare cases of quetiapine overdose leading to an increased QTc interval, death, or coma. In patients with a history of severe cardiovascular diseases, the risk of developing hypotension during an overdose may increase (see the "Special Precautions" section).Symptoms Symptoms noted during overdose were primarily the result of the enhancement of known pharmacological effects of quetiapine, such as drowsiness and sedation, tachycardia, decreased blood pressure, and anticholinergic effects.Treatment There are no specific antidotes for quetiapine. In cases of severe intoxication, consider the possibility of overdose with multiple medications. It is recommended to implement measures aimed at maintaining respiratory and cardiovascular function, ensuring adequate oxygenation and ventilation.Reports have been published of the resolution of severe central nervous system (CNS) hypotension, including coma, delirium, and overt anticholinergic syndrome, following intravenous administration of physostigmine (at a dose of 1-2 mg) under continuous electrocardiogram (ECG) monitoring.In cases of refractory arterial hypotension during quetiapine overdose, treatment should be conducted through intravenous fluid administration and/or sympathomimetic agents (epinephrine and dopamine should not be administered, as stimulation of β-adrenergic receptors may exacerbate the decrease in blood pressure against the blockade of α-adrenergic receptors by quetiapine).Gastric lavage (after intubation if the patient is unconscious) and the administration of activated charcoal and laxatives may help eliminate unabsorbed quetiapine; however, the effectiveness of these measures has not been studied.Close medical monitoring should continue until the patient's condition improves.Caution should be exercised when combining Quetiapine Canon with other CNS-active medications, as well as with alcohol. Caution is advised for patients taking other antagonists of cholinergic (muscarinic) receptors (see the "Special Precautions" section). The isoenzyme of the cytochrome P450 3A4 system is the main isoenzyme responsible for the metabolism of quetiapine, which occurs through the cytochrome P450 system. In healthy volunteers, the simultaneous administration of quetiapine (at a dose of 25 mg) with ketoconazole, an inhibitor of the CYP3A4 isoenzyme, resulted in an increase in the area under the concentration-time curve (AUC) of quetiapine by 5-8 times. Therefore, the simultaneous use of quetiapine and CYP3A4 isoenzyme inhibitors (ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin, etc.) is contraindicated. It is also not recommended to take quetiapine with grapefruit juice. In a pharmacokinetic study, the repeated administration of quetiapine before or simultaneously with carbamazepine led to a significant increase in the clearance of quetiapine and, consequently, a decrease in AUC, on average by 13%, compared to the administration of quetiapine without carbamazepine. In some patients, the decrease in AUC was even more pronounced. This interaction is accompanied by a reduction in quetiapine plasma concentration and may decrease the effectiveness of quetiapine therapy. The simultaneous use of quetiapine with phenytoin, another inducer of hepatic microsomal enzymes, was associated with an even more pronounced (approximately 450%) increase in the clearance of quetiapine. The use of quetiapine in patients receiving inducers of hepatic microsomal enzymes is only possible if the expected benefit of quetiapine therapy outweighs the risk associated with the discontinuation of the microsomal enzyme-inducing drug. Changes in the dosage of microsomal enzyme inducers should be gradual. If necessary, they may be replaced with drugs that do not induce hepatic microsomal enzymes (for example, valproic acid preparations). Quetiapine did not induce hepatic microsomal enzymes involved in the metabolism of phenazone. The pharmacokinetics of quetiapine were not significantly altered when used simultaneously with the antidepressant imipramine (CYP2D6 isoenzyme inhibitor) or fluoxetine (CYP3A4 and CYP2D6 isoenzyme inhibitors). The pharmacokinetics of quetiapine were not significantly altered when used simultaneously with antipsychotic medications risperidone or haloperidol. However, the simultaneous administration of quetiapine and thioridazine led to an approximately 70% increase in the clearance of quetiapine. The pharmacokinetics of quetiapine were not significantly altered when used simultaneously with cimetidine. With a single dose of 2 mg of lorazepam while taking quetiapine at a dose of 250 mg twice daily, the clearance of lorazepam decreased by approximately 20%. The pharmacokinetics of lithium preparations are not altered when used simultaneously with quetiapine. No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine were noted when sodium valproate and quetiapine were used together. Pharmacokinetic studies investigating the interaction of quetiapine with medications used for cardiovascular diseases have not been conducted. Caution should be exercised when combining quetiapine with medications that may cause electrolyte imbalance and prolong the QT interval. Patients taking quetiapine have reported false-positive results in screening tests for methadone and tricyclic antidepressants using immunoassay methods. To confirm screening results, chromatographic testing is recommended.

Mechanism of Action:
Quetiapine is an atypical antipsychotic medication.
Quetiapine and its active metabolite N-desalkylquetiapine (norquetiapine) interact with a wide range of neurotransmitter receptors in the brain. Quetiapine and N-desalkylquetiapine exhibit high affinity for serotonin receptors (5HT2) and dopamine receptors (D1 and D2) in the brain. It is believed that this combination of receptor antagonism, with greater selectivity for 5HT2 compared to D2 receptors, accounts for the primary clinical antipsychotic properties of quetiapine and the low incidence of extrapyramidal side effects (EPS) compared to typical antipsychotic agents.
Quetiapine and norquetiapine do not show significant affinity for benzodiazepine receptors but have high affinity for histamine and α1-adrenergic receptors and moderate affinity for α2-adrenergic receptors.
Additionally, quetiapine has no or low affinity for muscarinic receptors, while norquetiapine exhibits moderate to high affinity for several subtypes of muscarinic receptors, which explains the anticholinergic (muscarinic-like) effects of the drug.
Quetiapine has no affinity for the norepinephrine transporter and has low affinity for the 5HT1A serotonin receptor, while N-desalkylquetiapine shows high affinity for both. Inhibition of the norepinephrine transporter and partial agonism at 5HT1A serotonin receptors exhibited by N-desalkylquetiapine may account for the antidepressant effect of the drug. The specific contribution of the metabolite N-desalkylquetiapine to the pharmacological activity of quetiapine is not established.
Pharmacodynamics:
Pharmacodynamic Effects
Quetiapine demonstrates activity in tests for antipsychotic efficacy, such as conditioned reflex avoidance. It also blocks the action of dopamine agonists, assessed either in behavioral or electrophysiological studies, and increases concentrations of dopamine metabolites, a neurochemical marker of D2 receptor blockade.
Results from studies on extrapyramidal symptoms (EPS) in preclinical research showed that quetiapine differs from standard antipsychotic agents and has an atypical profile. Quetiapine does not induce increased sensitivity of dopamine D2 receptors with prolonged use. Quetiapine causes weak catalepsy at doses that effectively block D2 receptors. Quetiapine selectively acts on the limbic system, causing depolarization blockade of mesolimbic but not nigrostriatal dopaminergic neurons. With both short-term and long-term administration, quetiapine had minimal ability to induce dystonia in capuchin monkeys sensitized to haloperidol or untreated.
Clinical Efficacy
Quetiapine is effective against both positive and negative symptoms of schizophrenia.
Quetiapine is effective as monotherapy for manic episodes of moderate to severe intensity. Data on the long-term use of quetiapine for the prevention of subsequent manic and depressive episodes are lacking.
Data on the use of quetiapine in combination with sodium valproate or lithium preparations for manic episodes of moderate to severe intensity are limited; however, this combination therapy was generally well tolerated.
Additionally, quetiapine at doses of 300 mg and 600 mg is effective in patients with bipolar disorder type I and II of moderate to severe intensity. The efficacy of quetiapine at doses of 300 mg and 600 mg per day is comparable.
Quetiapine is effective in patients with schizophrenia and mania when taken twice daily, despite the half-life (T1/2) of quetiapine being approximately 7 hours. The effect of quetiapine on 5HT2 and D2 receptors lasts up to 12 hours after administration.
When quetiapine is administered with dose titration for schizophrenia, the incidence of EPS and concomitant use of m-cholinoblockers was comparable to that with placebo. When quetiapine is prescribed in fixed doses ranging from 75 to 750 mg/day to patients with schizophrenia, the incidence of EPS and the need for concomitant use of m-cholinoblockers did not increase.
When quetiapine is used at doses up to 800 mg/day for the treatment of manic episodes of moderate to severe intensity, both as monotherapy and in combination with lithium or sodium valproate, the incidence of EPS and concomitant use of m-cholinoblockers was comparable to that with placebo.

Absorption
Quetiapine is well absorbed from the gastrointestinal tract (GIT). Food intake does not significantly affect the bioavailability of quetiapine. The steady-state molar concentration of the active metabolite N-desalkylquetiapine is 35% of that of quetiapine.
The pharmacokinetics of quetiapine is linear.

Distribution
Binding to plasma proteins is 83%.

Metabolism
In vitro studies have shown that the CYP3A4 isoenzyme is the key isoenzyme in the metabolism of quetiapine mediated by the cytochrome P450 system. N-desalkylquetiapine is formed and eliminated with the involvement of the CYP3A4 isoenzyme. Quetiapine and some of its metabolites (including N-desalkylquetiapine) exhibit weak inhibitory activity towards the isoenzymes of the cytochrome P450 system 1A2, 2C9, 2C19, 2D6, and 3A4, but only at concentrations 5-50 times higher than those observed at the typically used effective dose of 300-800 mg/day.
Based on the results of in vitro studies, it should not be expected that the concomitant use of quetiapine with other drugs will lead to clinically significant inhibition of the metabolism of other medications mediated by the cytochrome P450 system.

Elimination
The half-life (T1/2) of quetiapine and N-desalkylquetiapine is approximately 7 hours and 12 hours, respectively.
Approximately 73% of quetiapine is eliminated by the kidneys and 21% through the intestines. Quetiapine is actively metabolized in the liver, with less than 5% of quetiapine undergoing no metabolism and being excreted unchanged by the kidneys or through the intestines. On average, less than 5% of the molar dose of free quetiapine and N-desalkylquetiapine in plasma is eliminated by the kidneys.

Pharmacokinetics in Different Patient Groups
Sex
No differences in pharmacokinetic parameters have been observed between men and women.

Elderly Patients
The average clearance in elderly patients is 30-50% lower than in patients aged 18 to 65 years.

Renal Impairment
The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m² body surface area), but individual clearance values are within the range observed in healthy volunteers.

Hepatic Impairment
In patients with liver failure (compensated alcoholic cirrhosis), the average plasma clearance of quetiapine is reduced by approximately 25%. Since quetiapine is extensively metabolized in the liver, an increase in plasma concentration of quetiapine may occur in patients with liver failure, necessitating dose adjustment.