Quetiapine-SZ 25 mg 60 tablets, film-coated

• Treatment of schizophrenia.

• Treatment of manic episodes in the context of bipolar disorder.

• Treatment of 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.

Quetiapine can be taken regardless of food intake.
Adults
Treatment of schizophrenia
Quetiapine 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 daily dose is 750 mg.
Treatment of manic episodes in bipolar disorder
Quetiapine is used as monotherapy or in combination with mood stabilizers.
Quetiapine 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 daily dose is 800 mg.
Treatment of depressive episodes in bipolar disorder
Quetiapine 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 daily dose of Quetiapine is 600 mg.
The antidepressant effect of Quetiapine has been confirmed at doses of 300 and 600 mg/day. In short-term therapy, the efficacy of Quetiapine at doses of 300 and 600 mg/day was comparable (see "Pharmacodynamics" section).
Elderly
In elderly patients, the initial dose of Quetiapine is 25 mg/day. The dose should be increased daily by 25-50 mg until an effective dose is reached, which is likely to be lower than that in younger patients.
Patients with renal insufficiency
Dose adjustment is not required.
Patients with hepatic insufficiency
Quetiapine is extensively metabolized in the liver. Therefore, caution should be exercised when administering Quetiapine to patients with hepatic insufficiency, especially at the beginning of therapy. It is recommended to start therapy with Quetiapine at 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, equivalent to quetiapine - 25 mg;
excipients (core): microcrystalline cellulose - 60.0 mg, lactose monohydrate (milk sugar) - 44.0 mg, povidone (medium molecular weight polyvinylpyrrolidone) - 9.0 mg, croscarmellose sodium (primellose) - 10.5 mg, magnesium stearate - 1.5 mg;
excipients (coating): Opadry II (partially hydrolyzed polyvinyl alcohol - 2.0 mg, polyethylene glycol 3350 - 1.01 mg, talc - 0.74 mg, titanium dioxide E 171 - 1.1333 mg, iron oxide (II) yellow E 172 - 0.1167 mg).

Film-coated tablets from beige-yellow to beige in color, round, biconvex. The tablets are white or almost white in cross-section.

Increased sensitivity to any of the components of the drug, including lactase deficiency, glucose-galactose malabsorption, and galactose intolerance.
Concurrent use with cytochrome P450 inhibitors, such as azole antifungals, erythromycin, clarithromycin, and nefazodone, as well as protease inhibitors (see the "Interaction with other medicinal products" section).
Although the efficacy and safety of Quetiapine in children and adolescents aged 10-17 years have been studied in clinical trials, the use of Quetiapine in patients under 18 years of age is not indicated.
Use with caution:
In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, elderly patients, hepatic insufficiency, and a history of seizures.
Pregnancy and lactation:
The safety and efficacy of Quetiapine in pregnant women have not been established. Therefore, during pregnancy, Quetiapine may be used only if the expected benefit to the woman justifies the potential risk to the fetus.
The extent of Quetiapine excretion in breast milk is unknown. Women should be advised to avoid breastfeeding while taking Quetiapine.

Drowsiness
During therapy with Quetiapine, drowsiness and related symptoms, such as sedation, may occur (see "Side Effects" section). 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 side effect was generally mild to moderate. If significant drowsiness occurs, patients with depression in the context of bipolar disorder may require more frequent doctor visits for 2 weeks from the onset of drowsiness or until the severity of symptoms decreases. In some cases, discontinuation of Quetiapine 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 hypotension. Orthostatic hypotension may occur during Quetiapine therapy, especially during dose titration at the beginning of treatment. If orthostatic hypotension occurs, dose reduction or slower titration may be required.
Seizures
No differences in the frequency of seizures were found in patients taking Quetiapine or placebo. However, as with therapy using other antipsychotic medications, caution is recommended when treating patients with a history of seizures (see "Side Effects" section).
Extrapyramidal Symptoms
An increased frequency of EPS has been noted in adult patients with depression in the context of bipolar disorder when taking Quetiapine for depressive episodes compared to placebo (see "Side Effects" section).
Tardive Dyskinesia
If symptoms of tardive dyskinesia develop, it is recommended to reduce the dose of the medication or gradually discontinue it (see "Side Effects" section).
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome may develop during the use of antipsychotic medications, including Quetiapine (see "Side Effects" section). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system lability, and increased creatine phosphokinase activity. In such cases, Quetiapine must be discontinued, and appropriate treatment should be provided.
Severe Neutropenia
In clinical studies of Quetiapine, cases of severe neutropenia (neutrophil count

The most common side effects of Quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia.
The use of Quetiapine, like other antipsychotic medications, may be accompanied by weight gain, fainting, the development of malignant neuroleptic syndrome, leukopenia, neutropenia, and peripheral edema.
The frequency of adverse reactions is presented in the following gradation: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), unspecified frequency. Very common (≥ 1/10) From the central nervous system: dizziness, drowsiness, headache From the gastrointestinal tract: dry mouth General disorders: withdrawal syndrome Changes in laboratory and instrumental indicators: increased triglyceride levels, total cholesterol (mainly low-density lipoprotein cholesterol - LDL) Common (≥ 1/100, < 1/10) From the hematopoietic system: leukopenia From the central nervous system: dysarthria, unusual and nightmare dreams, fainting, extrapyramidal symptoms From the cardiovascular system: tachycardia, orthostatic hypotension From the visual organ: blurred vision From the respiratory system: rhinitis From the gastrointestinal tract: constipation, dyspepsia General disorders: mild asthenia, peripheral edema Changes in laboratory and instrumental indicators: weight gain, increased liver transaminase activity (AST, ALT), decreased neutrophil count, hyperglycemia Uncommon (≥ 1/1000, < 1/100) From the blood system: eosinophilia From the immune system: hypersensitivity reactions From the central nervous system: seizures, restless legs syndrome From the gastrointestinal tract: dysphagia Changes in laboratory and instrumental indicators: increased creatine phosphokinase activity not associated with malignant neuroleptic syndrome, thrombocytopenia Rare (≥ 1/10,000, < 1/1000) From the gastrointestinal tract: jaundice From the reproductive system: priapism General disorders: malignant neuroleptic syndrome Changes in laboratory and instrumental indicators: increased creatine phosphokinase activity Very rare (< 1/10,000) From the immune system: anaphylactic reactions Metabolic disorders: diabetes mellitus From the central nervous system: tardive dyskinesia From the gastrointestinal tract: hepatitis From the skin and subcutaneous tissue: angioedema, Stevens-Johnson syndrome Unspecified frequency From the hematopoietic system: neutropenia 1. See the "Special Instructions" section 2. Drowsiness usually occurs within the first 2 weeks after starting therapy and typically resolves with continued use of Quetiapine. 3. Asymptomatic increases in AST, ALT, and GGT activity in the serum may occur, usually reversible with continued use of Quetiapine. 4. Like other antipsychotic medications and α1-adrenergic blockers, 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 decompensation of diabetes mellitus have been reported. 6. The frequency of this side effect was assessed based on post-marketing surveillance results. 7. An increase in fasting blood glucose ≥126 mg/dL (≥7.0 mmol/L) or postprandial blood glucose ≥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. Primarily occurs at the beginning of therapy. 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 patientsThere 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 the intake of 6 g of quetiapine during post-marketing studies 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 increased QTc interval, death, or coma. In patients with a history of severe cardiovascular diseases, the risk of developing side effects from overdose may increase (see "Special Precautions" section).Symptoms noted in overdose cases were primarily the result of the enhancement of the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia, and decreased blood pressure. There are no specific antidotes for quetiapine. In cases of severe intoxication, it is important to 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. 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 with other drugs that affect the central nervous system, as well as with alcohol. Cytochrome P450 (CYP)3A4 is the main isoenzyme responsible for the metabolism of quetiapine, which occurs through the cytochrome P450 system. In studies on healthy volunteers, the concomitant administration of quetiapine (at a dose of 25 mg) with ketoconazole, a CYP3A4 inhibitor, resulted in an increase in the area under the concentration-time curve (AUC) of quetiapine by 5-8 times. Therefore, the concomitant use of quetiapine and CYP3A4 inhibitors is contraindicated. It is also not recommended to take quetiapine with grapefruit juice. In a pharmacokinetic study, the administration of quetiapine at various dosages 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 concomitant administration of quetiapine with phenytoin, another inducer of the microsomal liver system, was associated with an even more pronounced (approximately 450%) increase in the clearance of quetiapine. The administration of quetiapine to patients receiving inducers of the liver enzyme system is only possible if the expected benefit of quetiapine therapy outweighs the risk associated with the withdrawal of the enzyme-inducing drug. Changes in the dosage of enzyme-inducing drugs should be gradual. If necessary, they may be replaced with drugs that do not induce microsomal enzymes (e.g., valproic acid preparations). The pharmacokinetics of quetiapine were not significantly altered when administered simultaneously with the antidepressant imipramine (CYP2D6 inhibitor) or fluoxetine (CYP3A4 and CYP2D6 inhibitor). The pharmacokinetics of quetiapine were not significantly altered when administered simultaneously with antipsychotic medications risperidone or haloperidol. However, the simultaneous intake of quetiapine and thioridazine led to an increase in the clearance of quetiapine by approximately 70%. The pharmacokinetics of quetiapine were not significantly altered when administered 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 quetiapine is administered simultaneously. No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine were noted when sodium valproate and quetiapine were administered together. Pharmacokinetic studies investigating the interaction of quetiapine with drugs used for cardiovascular diseases have not been conducted. Caution should be exercised when combining quetiapine with drugs that can cause electrolyte imbalance and prolong the QTc interval. Quetiapine did not induce liver enzyme systems involved in the metabolism of phenazone.

Mechanism of Action
Quetiapine is an atypical antipsychotic medication. Quetiapine and its active metabolite N-desalkyl quetiapine interact with neurotransmitter receptors in the brain. Quetiapine and N-desalkyl quetiapine exhibit high affinity for serotonin receptors of the 5HT2 type and dopamine receptors of the D1 and D2 types in the brain. The higher selectivity for 5HT2 serotonin receptors compared to D2 dopamine receptors accounts for the primary clinical antipsychotic properties of Quetiapine and the low incidence of extrapyramidal side effects. Additionally, N-desalkyl quetiapine shows high affinity for the norepinephrine transporter. Quetiapine and N-desalkyl quetiapine have high affinity for histamine and α1-adrenergic receptors and lower affinity for α2-adrenergic receptors and 5HT1 serotonin receptors.
Quetiapine does not exhibit significant affinity for cholinergic muscarinic and benzodiazepine receptors.
In standard tests, quetiapine demonstrates antipsychotic activity. The specific contribution of the metabolite N-desalkyl quetiapine to the pharmacological activity of quetiapine has not been established.
Studies on extrapyramidal symptoms (EPS) in animals revealed that quetiapine induces weak catalepsy at doses that effectively block D2 receptors. Quetiapine causes a selective reduction in the activity of mesolimbic A10 dopaminergic neurons compared to A9 nigrostriatal neurons involved in motor function.
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 is generally well tolerated. Additionally, quetiapine at doses of 300 mg and 600 mg is effective in patients with bipolar disorder types 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 of quetiapine being approximately 7 hours. The effect of quetiapine on 5HT2 and D2 receptors lasts up to 12 hours after administration.
Quetiapine does not cause a prolonged increase in plasma prolactin levels. In studies with various fixed doses of the drug, no differences in prolactin levels were found between quetiapine and placebo. Prolactin levels with different fixed doses of quetiapine did not differ from those with placebo.
When quetiapine is administered with dose titration for schizophrenia, the frequency of EPS and concomitant use of anticholinergic medications 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 anticholinergic medications 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 frequency of EPS and concomitant use of anticholinergic medications was comparable to that with placebo.

When administered orally, quetiapine is well absorbed from the gastrointestinal tract and is actively metabolized in the liver.
Food intake does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine binds to plasma proteins.
The steady-state molar concentration of the active metabolite N-desalkyl quetiapine is 35% of that of quetiapine. The half-life of quetiapine and N-desalkyl quetiapine is about 7 and 12 hours, respectively. The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear, with no observed differences in pharmacokinetic parameters between men and women.
The average clearance of quetiapine in elderly patients is 30-50% lower than in patients aged 18 to 65 years.
The average plasma clearance of quetiapine decreases by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m²), but individual clearance values are within the range observed in healthy volunteers. In patients with liver impairment (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 impairment, necessitating dose adjustment.
On average, less than 5% of the molar dose of free quetiapine and N-desalkyl quetiapine in plasma is excreted in urine. Approximately 73% of quetiapine is excreted in urine and 21% in feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or in feces.
CYP3A4 has been established as the key isoenzyme in the metabolism of quetiapine mediated by cytochrome P450. N-desalkyl quetiapine is formed with the involvement of the CYP3A4 isoenzyme.
Quetiapine and some of its metabolites (including N-desalkyl quetiapine) exhibit weak inhibitory activity towards cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4, but only at concentrations 5-50 times higher than those observed at the typically used effective dosage of 300-800 mg/day.
Based on in vitro results, co-administration of quetiapine with other drugs is not expected to lead to clinically significant inhibition of the metabolism of other medications mediated by cytochrome P450.