Seroquel - instructions for use, dose, side effects, contraindications

Composition:One tablet, film-coated, 25 mg contains:
Active substance: quetiapine fumarate 28.78 mg (equivalent to 25.00 mg quetiapine base).
Excipients: povidone 7.00 mg, calcium hydrophosphate 8.72 mg, microcrystalline cellulose 28.50 mg, sodium carboxymethyl starch 7.00 mg, lactose monohydrate 19.00 mg, magnesium stearate 1.00 mg; shell: hypromellose 1.56 mg, macrogol 400 0.31 mg, titanium dioxide 0.59 mg, iron oxide dye, yellow 0.02 mg, iron oxide dye, red 0.02 mg.
One tablet, film-coated, 100 mg contains:
Active substance: quetiapine fumarate 115.13 mg (equivalent to 100.00 mg quetiapine base).
Excipients: Povidone 10.00 mg, calcium hydrophosphate 10.00 mg, microcrystalline cellulose 73.07 mg, sodium carboxymethyl starch 18.00 mg, lactose monohydrate 20.70 mg, magnesium stearate 3.10 mg; membrane: hypromellose 3.91 mg, macrogol 400 0.78 mg, titanium dioxide 0.12 mg, iron oxide dye, yellow 1.44 mg.
One tablet, film-coated, 200 mg contains: Active substance: quetiapine fumarate 230.26 mg (equivalent to 200.00 mg quetiapine base).
Excipients: povidone 20.00 mg, calcium hydrophosphate 20.00 mg, microcrystalline cellulose 146.14 mg, sodium carboxymethyl starch 36.00 mg, lactose monohydrate 41.40 mg, magnesium stearate 6.20 mg; shell: hypromellose 7.81 mg, macrogol 400 1.56 mg, titanium dioxide 3.13 mg.

Description:25 mg tablet: round, biconvex tablet of pink color, covered with a film membrane; with engraving SEROQUEL 25 on one side;
100 mg tablet: a round, biconvex tablet of yellow color, covered with a film membrane; with engraving SEROQUEL 100 on one side;
200 mg tablet: round, biconvex tablet of white color, film-coated; with engraving SEROQUEL 200 on one side.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic).

ATX: & nbsp

N.05.A.H.04 Quetiapine

Pharmacodynamics:Mechanism of action
Quetiapine is an atypical antipsychotic. Quetiapine and its active metabolite N-desalkylkvetiapine (norquetiapine) interact with a wide range of neutron-transmitting receptors in the brain. Quetiapine and N-desalkylketiapine show a high affinity for 5HT₂-serotonin receptors and D₁ - and D₂dopamine receptors of the brain. Antagonism to these receptors in combination with a higher selectivity to 5HT₂serotonin receptors, than to D₂- dopamine receptors, determines the clinical antipsychotic properties of the Seroquel® preparation and the low incidence of extrapyramidal side effects. Quetiapine has no affinity for the carrier of noradrenaline and has a low affinity for 5HT_1A-serotonin receptor, while N-dealkylkvetiapine exhibits a high affinity for both. Norepinephrine transporter inhibition and partial agonism with respect to 5HT_1A-serotonin receptors, manifested by N-dezalkylkvetiapine, may cause the antidepressant effect of the Seroquel® preparation. Quetiapine and N-desalkylketiapine have a high affinity for histamine and α₁-adrenoceptors and moderate affinity for α₂adrenoreceptors. Besides quetiapine has no or low affinity for muscarinic receptors, while N-dealkylketiapine exhibits moderate or high affinity forseveral subtypes of muscarinic receptors.
In standard tests quetiapine has antipsychotic activity.
The specific contribution of the N-dezalkylkvetiapine metabolite to the pharmacological activity of quetiapine is not established. The results of the study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes a weak catalepsy in doses effectively blocking D₂ receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10-dopaminergic neurons in comparison with A9-nigrostriate neurons involved in motor function.
Efficiency
The drug Seroquel® is effective against both positive and negative symptoms of schizophrenia.
The drug Seroquel® is effective as a monotherapy for manic episodes from moderate to severe severity. Data on the long-term use of the Seroquel® preparation for the prevention of subsequent manic and depressive episodes are absent. Data on the use of Seroquel® in combination with valproate semiotria or lithium preparations for moderate to severe manic episodes are limited, but this combination therapy was generally well tolerated.In addition, the drug Seroquel® in a dose of 300 mg and 600 mg is effective in patients with type I and II bipolar disorder from moderate to severe severity. At the same time, the effectiveness of the Seroquel® preparation when taken at a dose of 300 mg and 600 mg per day is comparable.
The drug Seroquel® is effective in patients with schizophrenia and mania when taking the drug 2 times a day, despite the fact that the half-life of quetiapine is about 7 hours. The effect of quetiapine on 5HT₂- and D₂- receptors lasts up to 12 hours after taking the drug.
When taking Seroquel® with a dose titration in schizophrenia, the frequency of EPS and concomitant use of m-holinoblockers was comparable to that of placebo. When prescribing Seroquel® in fixed doses from 75 to 750 mg / day. patients with schizophrenia, the incidence of EPS and the need for concomitant use of m-holinoblokatorov did not increase.
When using Seroquel ® in doses up to 800 mg / day. for the treatment of manic episodes from moderate to severe severity, either as monotherapy or in combination with lithium preparations or valproate semitrium, the incidence of EPS and concomitant use of m-holinoblockers was comparable to that of placebo.

Pharmacokinetics:When administered orally quetiapine well absorbed from the gastrointestinal tract and actively metabolized in the liver.
The intake of food does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine binds to plasma proteins.
The equilibrium molar concentration of the active metabolite N-dealkyl quetiapine is 35% of that of quetiapine. The half-life of quetiapine and N-dealkyl quetiapine is approximately 7 and 12 hours, respectively. The pharmacokinetics of quetiapine and N-dealkyl quetiapine are linear, there is no difference in pharmacokinetic parameters between men and women.
The average clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.
The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min / 1.73 m2), but individual clearance rates are within the values found in healthy volunteers. In patients with hepatic insufficiency (compensated alcoholic cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%. Because the quetiapine is intensively metabolized in the liver, in patients with hepatic insufficiency it is possible to increase the plasma concentration of quetiapine, which requires a dose adjustment.
On average, less than 5% of the molar dose of the fraction of free quetiapine and N-dealkyl quetiapine plasma is excreted in the urine. Approximately 73% of quetiapine is excreted in urine and 21% with feces. Less than 5% of quetiapine is not metabolized and is excreted unchanged by kidneys or feces.
It was found that CYP3A4 is the key isoenzyme of quetiapine metabolism, mediated by cytochrome P450. N-dealkyl quetiapine is formed with the participation of the CYP3A4 isoenzyme.
Quetiapine and some of its metabolites (including N-dealkyl quetiapine) have a weak inhibitory activity against cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 isoenzymes, but only at concentrations 5-50 times higher than the concentrations observed at the usual effective dosage of 300-800 mg / day.
Based on in vitro results, the simultaneous administration of quetiapine to other drugs should not be expected to lead to a clinically pronounced inhibition of the metabolism of other medicaments mediated by cytochrome P450.

Indications:- For the treatment of schizophrenia.
- For the treatment of manic episodes in the structure of bipolar disorder.
- For the treatment of depressive episodes from medium to severe severity in the structure of bipolar disorder.
The drug is not indicated for the prevention of manic and depressive episodes.

Contraindications:Hypersensitivity to any of the components of the drug, including lactase deficiency, glucose-galactose malabsorption and galactose intolerance.
Co-administration with cytochrome P450 inhibitors, such as antifungal agents of the azole group, erythromycin, clarithromycin and nefazodone, as well as HIV protease inhibitors (see "Interactions with Other Drugs and Other Interactions").
Despite the fact that the efficacy and safety of Seroquel® in children and adolescents aged 10-17 years have been studied in clinical trials, the use of Seroquel® in patients under the age of 18 years is not indicated.

Carefully:In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, elderly age, hepatic insufficiency,convulsive fits in the anamnesis, the risk of stroke and aspiration pneumonia.

Pregnancy and lactation:The safety and efficacy of quetiapine in pregnant women have not been established. Therefore, during pregnancy quetiapine It can only be used if the expected benefit for a woman justifies the potential risk to the fetus.
When using antipsychotics, including quetiapine, in the third trimester of pregnancy, neonates have a risk of developing adverse reactions of varying severity and duration, including EPS and / or withdrawal syndrome. There was reported on excitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome or feeding disorders. In this regard, you should carefully monitor the condition of newborns. Quetiapine excretion with breast milk has been reported, but excretion has not been established. Women should be advised to avoid breastfeeding while taking quetiapine.

Dosing and Administration:The drug Seroquel® can be used regardless of food intake.
Adults
Treatment of schizophrenia
The drug Seroquel® is prescribed 2 times a day.The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg.
Starting from the 4th day, the dose should be selected to an effective dose, usually in the range of 300 to 450 mg / day. Depending on the clinical effect and individual patient tolerance, the dose may vary from 150 to 750 mg / day. The maximum recommended daily dose is 750 mg.
Treatment of manic episodes in the structure of bipolar disorder
The drug Seroquel ® is used as a monotherapy or in combination with drugs that have a normotimic effect.
The drug Seroquel® is prescribed 2 times a day. The daily dose for the first 4 days of therapy is: 1st day - 100 mg, 2nd day - 200 mg, 3rd day - 300 mg, 4th day - 400 mg. In the future, by the 6th day of therapy, the daily dose of the drug can be increased to 800 mg. The increase in the daily dose should not exceed 200 mg per day. Depending on the clinical effect and individual tolerability, the dose may vary from 200 to 800 mg / day. Usually the effective dose is from 400 to 800 mg / day. The maximum recommended daily dose is 800 mg.
Treatment of depressive episodes in the structure of bipolar disorder
The drug Seroquel® is prescribed once a day at night. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. The recommended dose is 300 mg / day. The maximum recommended daily dose of Seroquel® is 600 mg. The antidepressant effect of Seroquel® was confirmed when used at a dose of 300 and 600 mg / day. With short-term therapy, the effectiveness of Seroquel® in doses of 300 and 600 mg / day. was comparable (see the section "Pharmacodynamics").
Elderly
In elderly patients, the initial dose of Seroquel® is 25 mg / day. The dose should be increased daily by 25-50 mg until an effective dose is obtained, which is likely to be less than in young patients.
Patients with renal insufficiency
Correction of the dose is not required.
Patients with hepatic insufficiency
Quetiapine is extensively metabolized in the liver. Therefore, use caution when using Seroquel® in patients with liver failure, especially at the beginning of therapy. It is recommended to start therapy with Seroquel ® with a dose of 25 mg / day.and increase the dose daily by 25-50 mg until the effective dose is reached.

Side effects:The most common side effects of quetiapine (> 10%) are drowsiness, dizziness, dry mouth, withdrawal syndrome, increased triglyceride concentration, increased total cholesterol concentration (mainly low-density lipoprotein cholesterol-LDL cholesterol), a decrease in high-density lipoprotein cholesterol (HDL), weight gain, decreased hemoglobin concentration, and extrapyramidal symptoms.
The frequency of adverse reactions is given in the following gradation: very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), frequency, unspecified.

Often (≥1/10)
From the central nervous system:	Drelegation^1,^{4, 17}, drowsiness^2,17, headache, extrapyramidal symptoms^{1, 13}
From the gastrointestinal tract:	dry mouth
General disorders:	withdrawal syndrome^{1, 10}
Changes in laboratory and instrumental indicators:	^{Increase in the concentration of triglycerides, 1, 11, total cholesterol (mainly LDL cholesterol) 1.12, decrease in HDL cholesterol level, 18, weight gain9, decrease in hemoglobin concentration23}
Often (≥1/100, <1/10)
On the part of the hematopoiesis system:	lcolic^{1, 25}
From the central nervous system:	dysarthria, unusual and nightmarish dreams, increased appetite
From the cardiovascular system:	tazycardia^1,4, palpitations¹⁹, orthostatic gapoptosis^{1, 4, 17}
From the side of the organ of vision:	blurred vision
From the respiratory system:	dyspnea¹⁹
From the gastrointestinal tract:	constipation, indigestion, vomiting²¹
General disorders:	Mr.Significantly expressed asthenia, irritability, peripheral edema, fever
Changes in laboratory and instrumental indicators:	increased ALT activity³, an increase in GGT activity³, decrease in the number of neutrophils^1,22, an increase in the number of eosinophils²⁴, hyperglycemia^1,7, increased concentration of prolactin in the blood serum¹⁶, a decrease in the concentration of total and free T4²⁰, a decrease in the concentration of the total T3²⁰, increased concentration of TSH²⁰
Infrequently (≥1/1000, <1/100);
From the cardiovascular system:	bradycardia²⁶
From the immune system:	RHypersensitivity reactions
From the central nervous system:	convulsions¹, restless legs syndrome, tardive dyskinesia¹, faint^1,4,17
From the respiratory system:	rhinitis
From the gastrointestinal tract:	disfagia^1,⁸
From the side of the kidneys and urinary tract:	retention of urine
Changes in laboratory and instrumental indicators:	increased activity ACT³, thrombocytopenia¹⁴, lengthening the interval QT^1,13, decrease in the concentration of free T3²⁰
Rarely (≥1/10000, <1/1000)
From the liver and bile excretory ways:	jaundice⁶
On the part of reproductive system:	priapism, galactorrhea
General disorders:	malignant neuroleptic syndrome¹, hypothermia
Changes in laboratory and instrumental indicators:	increased activity of creatine phosphokinase¹⁵, agranulocytosis²⁷
From the central nervous system:	somnambulism and similar phenomena
From the gastrointestinal tract:	intestinal obstruction / ileus
Very rarely (<1/10000)
From the immune system:	anaphylactic reactions⁶
Metabolic violations:	diabetes^1,5,6
From the side of the liver and bile excretory ways:	hepatitis⁶
From the skin and subcutaneous tissues:	angioedema⁶, Stevens-Johnson syndrome⁶
Unspecified frequencies
On the part of the hematopoiesis system:	neutropenia¹
General disorders:	withdrawal syndrome in newborns²⁸

1. Refer to "Special instructions"
2.Drowsiness usually occurs within the first 2 weeks after initiation of therapy and is usually resolved against the backdrop of continued use of quetiapine.
3. There may be an asymptomatic increase (≥3 times the upper limit of the norm when measured at any time) of the activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) in serum, usually reversible against continued use of quetiapine.
4. Like other antipsychotics with α_1-adrenoblokiruyuschim action, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia, in some cases - fainting, especially at the beginning of therapy (see section "Special instructions").
5. Very rare cases of decompensation of diabetes mellitus have been noted.
6. The frequency of this side effect was estimated based on the results of post-marketing surveillance.
7. Increase in fasting blood glucose ≥ 126 mg / dl (≥ 7.0 mmol / l) or post-prandial blood glucose ≥ 200 mg / dL (≥ 11.1 mmol / L), at least once.
8. A higher incidence of dysphagia in quetiapine compared with placebo was noted only in patients with depression in the structure of bipolar disorder.
9.Increase in the initial body weight by at least 7%. Basically, it occurs at the beginning of therapy in adults.
10. In studying the 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 the "withdrawal" syndrome was significantly reduced 1 week after discontinuation of the drug.
11. Increase in the concentration of triglycerides ≥ 200 mg / dl (≥ 2.258 mmol / L) in patients ≥18 years of age or ≥ 150 mg / dL (≥ 1.694 mmol / L) in patients <18 years of age, at least once.
12. Increasing the total cholesterol concentration ≥ 240 mg / dl (≥ 6.2064 mmol / L) in patients ≥18 years of age or ≥ 200 mg / dL (≥ 5.172 mmol / L) in patients <18 years of age, at least once.
13. See further in the text of the Instruction.
14. Decreased platelet count ≤ 100 x10⁹/ l, at least for a single determination.
15. Without communication with a malignant neuroleptic syndrome. According to clinical studies.
16. Increase in prolactin concentration in patients ≥ 18 years of age:> 20 μg / L (≥ 869.56 pmol / L) in men; > 30 μg / l (≥ 1304.34 pmol / L) in women.
17. May lead to a fall.
18.Reduction in HDL cholesterol concentration <40 mg / dl (<1.03 mmol / l) in men and <50 mg / dL (<1.29 mmol / L) in women.
19. These phenomena are often noted against a background of tachycardia, dizziness, orthostatic hypotension and / or concomitant pathology of the cardiovascular or respiratory system.
20. Based on potentially clinically significant deviations from the normal baseline observed in all clinical trials. Changes in the concentration of total T4, free T4, total TK, free TK to <80% of the lower limit of the norm (pmol / L) when measured at any time. Change in the concentration of TTG> 5 mI / d when measured at any time.
21. Based on the increased incidence of vomiting in elderly patients (age ≥ 65 years).
22. In short-term clinical trials of monotherapy with quetiapine in patients with neutrophil count before therapy ≥1.5 x 10⁹ / l cases of neutropenia (number of neutrophils <1.5 x 10⁹ / l) were observed in 1.9% of patients in the quetiapine group versus 1.5% in the placebo group. Decrease in the number of neutrophils ≥0.5, but <1.0 x 10⁹ / l was noted with a frequency of 0.2% in the quetiapine group and placebo. Decrease in the number of neutrophils <0.5 x 10⁹ / l, even for a single determination, 0.21% of patients in the quetiapine group were compared to 0% in the placebo group.
23. Reduction of hemoglobin concentration ≤ 13 g / dl in males and ≤ 12 g / dl in females, at least once in 11% of patients on quetiapine in all clinical trials, including long-term therapy. In short-term placebo-controlled studies, a reduction in hemoglobin concentrations of ≤13 g / dl in males and ≤12 g / dl in females, at least once, was noted in 8.3% of patients in the quetiapine group compared with 6.2% in the group placebo.
24. Based on potentially clinically relevant deviations from the baseline normal level noted in all clinical trials. Increase in the number of eosinophils ≥1 x 10⁹ / l when measured at any time.
25. Based on the potentially clinically significant deviations from the baseline normal level noted in all clinical trials. Reducing the number of white blood cells ≤3 x 10⁹ / l when measured at any time.
26. May develop at or soon after initiation of therapy and be accompanied by hypotension and / or fainting. The frequency is based on reports of bradycardia and related adverse events in all clinical studies of quetiapine.
27.Based on the frequency assessment in patients who participated in all clinical studies of quetiapine who experienced severe neutropenia (<0.5 x 10⁹/ l) in combination with infections.
28. See the section "Pregnancy and lactation".
QT interval prolongation, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered side effects of neuroleptics.
ESR frequency in short-term clinical studies in adult patients with schizophrenia and mania in bipolar disorder structure was comparable in the placebo group and quetiapine (patients with schizophrenia: 7.8% quetiapine group and 8.0% in the placebo group; mania of bipolar disorder in the structure : 11.2% in the quetiapine group and 11.4% in the placebo group).
The incidence of EPS in short-term clinical trials in adult patients with depression in the structure of bipolar disorder in the quetiapine group was 8.9%, in the placebo group 3.8%. The frequency of individual symptoms of EPS (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 of the therapeutic groups.In long-term clinical studies of quetiapine in schizophrenia and bipolar disorder in adult patients, the incidence of EPS was comparable in quetiapine and placebo groups.
Against the background of quetiapine therapy, a dose-dependent decrease in the concentration of thyroid hormones can be noted. The frequency of potentially clinically significant changes in the concentration of thyroid hormones in short-term clinical trials 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 TZ -0.2% in the quetiapine group versus 0.0% in the placebo group. The change in TSH concentration was noted with a frequency of 3.2% in the quetiapine group and 2.7% in the placebo group. In short-term clinical trials of monotherapy, the frequency of potentially clinically significant changes in the concentration of TK and TSH was 0.0% in the quetiapine group and placebo; for T4 and TTG was 0.1% in the quetiapine group versus 0.0% in the placebo group. These changes, as a rule, are not associated with clinically pronounced hypothyroidism.The maximum decrease in total and free T4 was registered at the 6th week of quetiapine therapy, without further reduction in the concentration of hormones in long-term treatment. In almost all cases, the concentration of total and free T4 returned to baseline after quetiapine treatment was discontinued, regardless of the duration of treatment. The concentration of thyroxin-binding globulin (TSG) was unchanged when measured in 8 patients.

Overdose:A lethal outcome was reported with the admission of 13.6 g quetiapine in a patient who participated in the clinical study, as well as a lethal outcome after taking 6 g quetiapine in a post-marketing study of the drug. At the same time, the case of taking quetiapine in a dose exceeding 30 g is described, without a lethal outcome.
There are reports of extremely rare cases of quetiapine overdose leading to an increase in QTC interval, death or coma.
In patients with severe cardiovascular disease, the risk of developing side effects with an overdose may increase (see section "Special instructions").
Symptoms noted in overdose, in general,were a consequence of the enhancement of known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and lowering blood pressure.
Treatment
There are no specific antidotes to quetiapine. In cases of severe intoxication, one should remember about the possibility of an overdose with several medications. It is recommended to carry out activities aimed at maintaining the function of respiration and cardiovascular system, ensuring adequate oxygenation and ventilation. Reports have been published on the resolution of severe adverse effects from the central nervous system, including coma and delirium, after intravenous injection of physostigmine (1-2 mg) under constant ECG monitoring.
In case of occurrence of refractory hypotension in case of quetiapine overdose treatment should be carried out by intravenous fluid and / or sympathomimetic drugs (should not be prescribed epinephrine and dopamine, since stimulation of β-adrenergic receptors can cause an increase in hypotension while blocking α-adrenergic receptors with quetiapine).
Gastric lavage (after intubation, if the patient is unconscious) and the appointment of activated charcoal and laxatives
means can promote the removal of unabsorbed quetiapine, however, the effectiveness of these measures has not been studied. Close medical surveillance should continue until the patient's condition improves.

Interaction:Caution should be exercised in the combined use of quetiapine with other drugs that affect the central nervous system, as well as with alcohol.
Isozyme cytochrome P450 (CYP) 3A4 is the main isoenzyme responsible for the metabolism of quetiapine, which is carried out through the cytochrome P450 system. In healthy volunteers, co-administration of quetiapine (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 5-8 times.
Therefore, the combined use of quetiapine and inhibitors of the isoenzyme CYP3A4 is contraindicated. It is also not recommended to take quetiapine together with grapefruit juice.
In a pharmacokinetic study with multiple quetiapine administration prior to or concomitant with carbamazepine administration, a significant increase in quetiapine clearance and, correspondingly, a decrease in AUC, by an average of 13%, compared with quetiapine alone without carbamazepine. In some patients, the decrease in AUC was even more pronounced.This interaction is accompanied by a decrease in the concentration of quetiapine in plasma and may reduce the effectiveness of therapy with the drug Seroquel®. The combined use of the Seroquel® preparation with phenytoin, another inducer of microsomal liver enzymes, was accompanied by an even more pronounced (about 450%) increase in quetiapine clearance. The use of Seroquel® in patients receiving inductors of microsomal liver enzymes is possible only if the expected benefit of Seroquel® therapy exceeds the risk associated with the cancellation of the inductor preparation of microsomal liver enzymes.
The change in the dose of inductor preparations of microsomal liver enzymes should be gradual. If necessary, they can be replaced with drugs that do not induce microsomal liver enzymes (for example, preparations of valproic acid).
The pharmacokinetics of quetiapine did not change significantly with simultaneous use of an antidepressant imipramine (inhibitor of the isoenzyme CYP2D6) or fluoxetine (inhibitor of isoenzymes CYP3A4 and CYP2D6).
The pharmacokinetics of quetiapine does not change significantly when administered simultaneously with antipsychotic drugs risperidone or haloperidol.However, simultaneous administration of Seroquel® and thioridazine resulted in an increase in clearance of quetiapine by approximately 70%.
The pharmacokinetics of quetiapine does not change significantly with the simultaneous use of cimetidine.
With a single admission of 2 mg of lorazepam against quetiapine 250 mg twice daily, the clearance of lorazepam is reduced by approximately 20%.
The pharmacokinetics of lithium preparations does not change with simultaneous use of the Seroquel® preparation. There were no clinically significant changes in the pharmacokinetics of valproic acid and quetiapine in the combined use of semolife valproate and Seroquel® (quetiapine).
Pharmacokinetic studies on the interaction of the drug Seroquel® with drugs used in cardiovascular diseases have not been conducted. Caution should be exercised in the combined use of quetiapine and drugs capable of causing electrolyte imbalance and prolongation of the QTc interval.
Quetiapine did not induce the induction of microsomal liver enzymes involved in the metabolism of phenazone. In patients who took quetiapine, false-positive results of screening tests for the detection of methadone and tricyclic antidepressants by the method of enzyme immunoassay were noted. To confirm the results of screening, a chromatographic study is recommended.

Special instructions:Children and adolescents (aged 10 to 17 years)
Seroquel® is not indicated for use in children and adolescents under the age of 18 due to insufficient data on use in this age group. According to the results of clinical studies of quetiapine, some side effects (increased appetite, increased serum prolactin concentration, vomiting, runny nose and fainting) in children and adolescents were observed with a greater frequency than in adult patients. Some side effects (EPS) in children and adolescents may have different effects compared to older patients. There was also an increase in blood pressure, not observed in adult patients. In children and adolescents also observed a change in the function of the thyroid gland.
Influence on growth, puberty, mental development and behavioral reactions with prolonged use (more than 26 weeks) of quetiapine has not been studied.In placebo-controlled studies in children and adolescents with schizophrenia and mania in the structure of bipolar disorder, the incidence of EPS was higher with quetiapine compared with placebo.
Suicide / suicidal thoughts or clinical worsening
Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self harm and suicide (events related to suicide). This risk remains until the onset of severe remission. In view of the fact that before the improvement of the patient's condition from the beginning of treatment, several weeks or more may pass, patients should be under close medical supervision before the onset of improvement. According to the generally accepted clinical experience, the risk of suicide may increase in the early stages of the onset of remission. Patients (especially those at high risk for suicide) and their caregivers should be warned about the need to monitor clinical impairment, suicidal behavior or thoughts, unusual behavioral changes, and the need to consult a doctor immediately if they occur.
According to clinical studies in depressed patients with 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 for patients over 25 years of age.
Other psychiatric disorders for which therapy is prescribed quetiapineare also associated with an increased risk of suicidal events. In addition, such conditions can be comorbid with a depressive episode. Therefore, the precautions used in the therapy of patients with a depressive episode should be taken in the treatment of patients with other psychiatric disorders. With a sharp cessation of quetiapine therapy, the potential risk of suicidal events should be taken into account.
Patients with a history of suicidal events, as well as patients who clearly express suicidal thoughts before starting therapy, are at increased risk of suicidal intentions and suicidal attempts and should be carefully observed during treatment. A meta-analysis of placebo-controlled studies of antidepressants conducted by the FDA (Food and Drug Administration, USA)summarizing the data of some 4,400 children and adolescents and 7,700 adult patients with mental disorders, found an increased risk of suicidal behavior compared with placebo in children, adolescents and adults under the age of 25 years. This meta-analysis does not include studies where it was used quetiapine (see the section "Pharmacodynamics").
According to short-term placebo-controlled studies for all indications and in all age groups, the incidence of events associated with suicide was 0.8% for both quetiapine (76/9327) and placebo (37/4845).
In these studies in schizophrenic patients, the risk of suicidal events 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 older than 25 years; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under the age of 18 years.
In patients with mania in bipolar disorder, the risk of 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 older than 25 years; 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients under the age of 18 years.
Drowsiness
During therapy with Seroquel®, there may be drowsiness and related symptoms, for example sedation (see "Side effect"), In clinical trials involving patients with depression in the structure of bipolar disorder, drowsiness usually developed during the first three days of therapy. The severity of this side effect was mostly mild or moderate. With the development of severe drowsiness, patients with depression in the structure of bipolar disorder may need more frequent visits to the doctor within 2 weeks of the onset of drowsiness or to a decrease in the severity of symptoms. In some cases, discontinuation of Seroquel® therapy may be required.
Patients with cardiovascular diseases
Caution should be exercised in appointing quetiapine to patients with cardiovascular and cerebrovascular diseases, and other conditions predisposing to hypotension. On the background of quetiapine therapy, orthostatic hypotension may occur, especially during titration of the dose at the beginning of therapy.Orthostatic hypotension and related dizziness may increase the risk of accidental trauma (fall), especially in elderly patients. Patients should be cautious until they adapt to these potential side effects. If orthostatic hypotension occurs, a dose reduction or slower titration may be required.
Convulsive seizures
There were no differences in the incidence of seizures in patients who took quetiapine or placebo. However, as with other antipsychotic drugs, caution should be exercised in the treatment of patients with a history of seizures (see "Side effect").
Extrapyramidal symptoms
An increase in the incidence of EPS in patients with depression in the structure of bipolar disorder with quetiapine for depressive episodes compared with placebo has been noted (see "Side effect").
Against the background of taking quetiapine may occur akathisia, which is characterized by an unpleasant feeling of motor anxiety and the need to move,and is manifested by the patient's inability to sit or stand without movement. If such symptoms occur, do not increase the dose of quetiapine.
Late dyskinesia
In case of development of symptoms of tardive dyskinesia, it is recommended to reduce the dose of the drug or gradually cancel it (see the section "Side effect"). Symptoms of tardive dyskinesia may increase or even occur after discontinuation of the drug.
Malignant neuroleptic syndrome
Against the background of taking antipsychotic drugs, including quetiapine, can develop malignant neuroleptic syndrome (see the section "Side effect"). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, lability in the autonomic nervous system, increased activity of creatine phosphokinase. In such cases, it is necessary to cancel quetiapine and conduct appropriate treatment.
Severe neutropenia and agranulocytosis
In the short-term placebo-controlled clinical trials of monotherapy with quetiapine, cases of severe neutropenia (number of neutrophils <0.5 x 10⁹ / l) without infection.Agranulocytosis (severe neutropenia associated with infections) was reported in patients who received quetiapine in clinical trials (rarely), as well as in post-marketing (including fatal) cases. Most of these cases of severe neutropenia occurred several months after initiation of quetiapine therapy. It was not revealed
dose-dependent effect. Leukopenia and / or neutropenia were resolved after quetiapine therapy was discontinued. A possible risk factor for the onset of neutropenia is a previous lowered number of leukocytes and cases of drug-induced neutropenia in a history.
The development of agranulocytosis was also noted in patients without risk factors.
It is necessary to consider the possibility of developing neutropenia in patients with infection, especially in the absence of obvious predisposing factors, or in patients with unexplained fever; these cases should be conducted in accordance with clinical recommendations.
In patients with a neutrophil count <1.0 x 10⁹/ l, quetiapine should be discontinued.The patient should be observed to identify possible symptoms of infection and monitor the level of neutrophils (up to a level of 1.5 x 10⁹ / l).
Interaction with other drugs
Also see the section "Interaction with Other Drugs and Other Interactions". The use of quetiapine in combination with powerful inducers of microsomal liver enzymes, such as carbamazepine and phenytoin, helps to reduce the concentration of quetiapine in plasma and may reduce the effectiveness of therapy with the drug Seroquel®. The administration of the Seroquel® preparation to patients receiving inductors of microsomal liver enzymes is only possible if the expected benefit of Seroquel® therapy exceeds the risk associated with the cancellation of the inductor preparation of microsomal liver enzymes.
The change in the dose of inductor preparations of microsomal liver enzymes should be gradual. If necessary, they can be replaced with drugs that do not induce microsomal liver enzymes (eg, preparations of valproic acid).
Hyperglycaemia
Against the background of taking quetiapine may develop hyperglycemia or exacerbation of diabetes mellitus (in some cases - with the development of ketoacidosis or coma, including fatal), in patients with diabetes mellitus in history. It is recommended that patients who receive quetiapine and other neuroleptics, to identify possible symptoms of hyperglycemia, such as polyuria (increased urine output), polydipsia (pathologically increased thirst), polyphagia (increased appetite), and weakness. It is also recommended to monitor patients with diabetes mellitus and patients with risk factors for the development of diabetes mellitus to identify a possible deterioration in glycemic control (see section "Side effect"). Regular body weight should be monitored regularly.
Lipid content
Against the background of taking quetiapine may increase the concentration of triglycerides, cholesterol and LDL, as well as a decrease in the concentration of HDL (see section "Side effect").
Metabolic disorders
An increase in body weight, an increase in the concentration of glucose and lipids in the blood in some patients can lead to a deterioration in the metabolic profile, which requires appropriate monitoring.
QT interval extension
There was no correlation between the intake of quetiapine and the steady increase in the absolute value of the QT interval. However, the prolongation of the QT interval was noted with an overdose of the drug (see the section "Overdose"). Caution should be exercised when assigning quetiapine, as well as other antipsychotics, to patients with cardiovascular disease and the previously noted QT interval elongation. Caution should also be exercised in appointing quetiapine concomitantly with QTc-prolonging drugs, other antipsychotics, especially in the elderly, in patients with congenital QT prolongation, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see "Interaction with other drugs and other forms of interaction ").
Cardiomyopathy and myocarditis
During clinical trials and post-marketing use, cases of cardiomyopathy and myocarditis have been noted, but a causal relationship with the drug has not been established. It is necessary to evaluate the feasibility of quetiapine therapy in patients with suspected cardiomyopathy or myocarditis.
Acute reactions associated with drug withdrawal
With the sharp cancellation of quetiapine, the following acute reactions (withdrawal syndrome) can occur: nausea, vomiting, insomnia, headache, dizziness and irritability.
Therefore, it is recommended to cancel the drug gradually for at least one or two weeks.
Elderly patients with dementia
Seroquel® is not indicated for the treatment of psychoses associated with dementia.
Some atypical antipsychotics in randomized placebo-controlled trials increased the risk of developing cerebrovascular complications in patients with dementia approximately 3-fold. The mechanism of this increase in risk has not been studied. A similar risk of increasing the incidence of cerebrovascular complications can not be ruled out for other antipsychotic drugs or other groups of patients. Seroquel® should be used with
caution in patients at risk of stroke.
Analysis of the use of atypical neuroleptics for the treatment of psychoses associated with dementia in elderly patients revealed an increase in the mortality rate in the group of patients,
who received drugs of this group, compared with the placebo group.In addition, two 10-week, placebo-controlled trials 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 deaths observed in these patients were consistent with those expected for this population. There was no causal relationship between the treatment of quetiapine and the risk of increased mortality in elderly patients with dementia.
Disorders from the side of the liver
In the case of jaundice, Seroquel® should be discontinued.
Dysphagia
Dysphagia (see "Side effect") and aspiration were observed with quetiapine therapy. The causal relationship between the onset of aspiration pneumonia and the administration of quetiapine has not been established. However, care should be taken when prescribing the drug to patients at risk of aspiration pneumonia.
Venous thromboembolism
Against the background of taking neuroleptics, cases of venous thromboembolism were noted. Since patients taking antipsychotics often have risk factors for venous thromboembolism,Before and during treatment with antipsychotic drugs, including quetiapine, risk factors should be assessed and preventative measures taken.
Constipation and obstruction of the intestine
Constipation is a risk factor for intestinal obstruction. Against the background of the use of quetiapine, the development of constipation and intestinal obstruction was noted (see the "Side effect" section), including fatal cases in patients with a high risk of intestinal obstruction, including those receiving multiple concomitant medications that reduce intestinal motility, even in the absence of complaints for constipation.
Pancreatitis
During clinical trials and post-marketing use, cases of pancreatitis have been noted, but a causal relationship with the drug has not been established. In post-marketing messages,
that many patients had risk factors for developing pancreatitis, such as increased triglyceride concentrations (see subsection "Lipid Content"), cholelithiasis and alcohol use.
Additional Information
Data on the combined use of quetiapine with divalproex or lithium in acute manic episodes of mild or moderate severity are limited.A good tolerability of this combination therapy and an additive effect at the third week of therapy were noted.

Effect on the ability to drive transp. cf. and fur:Due to the impact on the central nervous system, quetiapine can affect the speed of psychomotor reactions and cause drowsiness. Therefore, during the period of treatment, patients are not recommended to work with mechanisms that require increased concentration of attention, including the management of vehicles is not recommended until individual tolerance of therapy is established.

Form release / dosage:Film coated tablets, 25 mg, 100 mg and 200 mg.

Packaging:When packing at AstraZeneca UK Limited, UK:
Tablets 25 mg, 100 mg, 200 mg: 10 tablets in Al / PVC blister, 6 blisters each in a cardboard box with instructions for use.
Tablets 25 mg + 100 mg + 200 mg: 10 tablets in Al / PVC blister (6 tablets of 25 mg, 3 tablets of 100 mg and 1 tablet of 200 mg), 1 blister in a cardboard pack with instructions for use.
When packing ZiO-ZAO at the enterprise:
Tablets 25 mg, 100 mg, 200 mg: 10 tablets in Al / PVC blister, 6 blisters each in a cardboard box with instructions for use.

Storage conditions:Store at temperatures below 30 ° C, in places inaccessible to children.

Shelf life:3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013468 / 01

Date of registration:21.11.2008 / 07.12.2016

Expiration Date:Unlimited

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

ASTRAZENECA UK, Ltd. United Kingdom

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp2016-12-27

Illustrated instructions

Instructions

Seroquel® (Seroquel®)