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

active substance: 57.56 mg quetiapine fumarate (equivalent to 50.00 mg quetiapine); Excipients: lactose monohydrate 125.72 mg, microcrystalline cellulose 125.72 mg, sodium citrate dihydrate 36.00 mg, hypromellose (2208) 150.00 mg, magnesium stearate 5.00 mg; film sheath: hypromellose (2910) 7.35 mg, macrogol 400 2.21 mg, titanium dioxide E171 2.72 mg, ferric oxide red oxide E172 0.11 mg, ferric oxide yellow oxide E172 0.11 mg.

Dosage of 150 mg:

active substance: 172.69 mg quetiapine fumarate (equivalent to 150,00 mg quetiapine);

Excipients: lactose monohydrate 74.65 mg, cellulose microcrystalline 74.65 mg, sodium citrate dihydrate 71.88 mg, hypromellose (2208) 172,50 mg, magnesium stearate 8.63 mg; film sheath: hypromellose (2910) 9.01 mg, macrogol 400 1.80 mg, titanium dioxide E171 3.60 mg.

Dosage 200 mg:

active substance: 230.26 mg quetiapine fumarate (equivalent to 200,00 mg quetiapine);

Excipients: lactose monohydrate 52.87 mg, microcrystalline cellulose 52.87 mg, sodium citrate dihydrate 75.00 mg, hypromellose (2208) 180.00 mg, magnesium stearate 9.00 mg; film sheath: hypromellose (2910) 8.82 mg, macrogol 400 2.65 mg, titanium dioxide E171 3.27 mg, ferric iron oxide yellow E172 0.26 mg.

Dosage of 300 mg:

active substance: 345.38 mg quetiapine fumarate (equivalent to 300.00 mg quetiapine); Excipients: lactose monohydrate 49.31 mg, cellulose microcrystalline 49.31 mg, sodium citrate dihydrate 100.00 mg, hypromellose (2208) 240.00 mg, magnesium stearate 16.00 mg; film membrane: hypromellose (2910) 11.77 mg, macrogol 400 3.53 mg, titanium dioxide E171 4.66 mg, iron dye oxide yellow E172 0.04 mg.

Dosage of 400 mg:

active substance: 460.50 mg quetiapine fumarate (equivalent to 400.00 mg quetiapine);

Excipients: lactose monohydrate 15.50 mg, microcrystalline cellulose 15.60 mg, sodium citrate dihydrate 100.00 mg, hypromellose (2208) 261.00 mg, magnesium stearate 17.40 mg; film membrane: hypromellose (2910) 13.63 mg, macrogol 400 2.73 mg, titanium dioxide E171 5.45 mg.

Description:

Tablet 50 mg: Oblong biconvex tablet of pink color, covered with a film membrane; with engraving XR 50 on one side;

Tablets 150 mg: Etcabouta double-lobed, biconvex tablet coated with film shell; with engraving XR 150 on one side;

Tablet 200 mg: Oblong biconvex tablet of yellow color, film-coated; with engraving XR 200 on one side;

Tablet 300 mg: Oblong biconvex tablet of light yellow color, covered with a film membrane; with engraving XR 300 on one side;

Tablet 400 mg: Oblong double-lobed tablet of white color, film-coated; with engraving XR 400 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-dezalkylkvetiapine (norquetiapine) interact with a wide range of neurotransmitter receptors in the brain. Quetiapine and N-dealkylketiapine show a high affinity for 5NT₂-serotonin receptors and D₁- and D₂dopamine receptors of the brain. Antagonism to these receptors in combination with a higher selectivity to 5NT₂- serotonin receptors, than to D₂- dopamine receptors,determines the clinical antipsychotic properties of the Seroquel® Prolong preparation and the low frequency of extrapyramidal undesirable reactions. Quetiapine has no affinity for the carrier of noradrenaline and has a low affinity for 5NT_1A-serotonin receptors, while N-dealkylketiapine exhibits a high affinity for them. Inhibition of the norepinephrine transporter and partial agonism in relation to 5NT_1A- serotonin receptors, manifested by N-desalkylkvetiapine, can cause antidepressant action of the drug Seroquel® Prolong. Quetiapine and N-desalkylketiapine have a high affinity for histamine and α₁adrenoreceptors and moderate affinity for α2adrenoreceptors. Besides, quetiapine has no or low affinity for muscarinic receptors, while N-desalkylkvetiapine exhibits moderate or high affinity for several subtypes of muscarinic receptors.

In standard tests in animals quetiapine has antipsychotic activity.

The specific contribution of the metabolite N-desalkylkvetiapine to the pharmacological activity of quetiapine is not established.The results of the study of extrapyramidal symptoms (EPS) in animals have revealed,

what 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.

In a short-term (9-week) study in patients without dementia aged 66 to 89 years (19% of patients were over 75 years old) with a large depressive disorder Seroquel® Prolong in doses of 50 mg to 300 mg per day (dose was adjusted for tolerance and clinical response, the average daily dose of the drug was 160 mg) reduced the severity of MADRS depression symptoms (Montgomery-Asberg Depression Rating Scale) (mean square change -7.54) compared with placebo. With the exception of the frequency of EPS, the tolerability of the Seroquel® Prolong preparation once a day in elderly patients was comparable to tolerability in patients aged 18-65 years.

The frequency of EPS and the increase in body weight in stable patients with schizophrenia does not increase with prolonged therapy with Seroquel® Prolong.

In studies of major depressive disorder according to criteria of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed) -. Reference Po Diagnostic and Statistical Manual of mental disorders, 4th edition) did not observe an increased risk of suicidal behavior and suicidal thinking while taking Seroquel drug ® Prolong versus placebo.

The two short-term (6-week) studies of combination therapy of a depressive episode Serokvel® Prolong drug at a dose of 150 mg / day and 300 mg / day with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine in patients with sub-optimal response to antidepressant monotherapy shown to improve symptoms of depression scale MADRS (rms change 2-3,3 points) compared with monotherapy antidepressant.

Pharmacokinetics:

Quetiapine is well absorbed from the gastrointestinal tract. The maximum concentration of quetiapine N-dezalkilkvetiapina plasma levels achieved after about 6 hours after ingestion Serokvel® Prolong. The equilibrium molar concentration of the active metabolite N-dealkylkvetiapine is 35% of that of quetiapine.

The pharmacokinetics of quetiapine and N-dealkylkvetiapine is linear and is dose-dependent when taking Seroquel® Prolong in a dose up to 800 mg once a day.

When taking Seroquel® Prolong, once a day at a dose equivalent to the daily dose of Seroquel®, taken in two doses, we observed similar areas under the concentration-time curve (AUC), but the maximum concentration in the plasma (C_mOh) was 13% less. Value AUC metabolite N- dezalkilkvetiapina was 8% less.

Studies on the effect of food intake on the bioavailability of quetiapine have shown that eating high-fat foods results in a statistically significant increase in C_max and AUC for the Seroquel® Prolong preparation is approximately 50% and 20%, respectively. Low-fat diet did not have a significant effect on C_max and AUC of quetiapine.

It is recommended to take Seroquel® Prolong once a day separately from food.

Approximately 83% of quetiapine binds to plasma proteins.

Determined that CYP3A4 is the key isoenzyme of quetiapine metabolism, mediated by cytochrome P450. N-zecalkylketiapine is formed with the participation of isoenzyme CYP3A4.

Quetiapine and some of its metabolites (including N-desalkylketiapine) have a weak inhibitory activity against cytochrome P450 1A2, 2C9, 2C19, 2 isoenzymesD6 and 3A4, but only at concentrations 5-50 times higher than the concentrations observed at the usual effective dose of 300-800 mg / day.

Based on the results in vitro, it should not be expected that simultaneous use of quetiapine with other drugs will lead to a clinically pronounced inhibition of the metabolism of other medicaments mediated by cytochrome P450.

The half-life of quetiapine and Nis about 7 and 12 hours, respectively. On average, less than 5% of the molar dose of the fraction of free quetiapine and N- Plasma deacylketetiapine is excreted in the urine. Approximately 73% of quetiapine is excreted in urine and 21% with feces. Quetiapine is actively metabolized in the liver, less than 5% of quetiapine is not metabolized and is excreted unchanged by kidneys or with feces.

Differences in pharmacokinetic parameters in men and women are not observed.

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 intensively metabolized in the liver, patients with liver failure may increase the plasma concentration of quetiapine, which requires dose adjustment.

Indications:

Schizophrenia, including the prevention of relapse in stable patients.

Bipolar disorders, including: moderate and severe manic episodes in the structure of bipolar disorder; severe episodes of depression in the structure of bipolar disorder; prevention of recurrence of bipolar disorders in patients with prior effective quetiapine therapy of manic or depressive episodes in the structure of bipolar disorder.

Depressive episode: combined therapy with suboptimal response to monotherapy with antidepressant.

Contraindications:

Hypersensitivity to any of the components of the drug.

Deficiency of lactase, 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 protease inhibitors (see "Interaction with other drugs and other interactions").

Despite the fact that the effectiveness and safety of Seroquel® Prolong in children and adolescents aged 10-17 years have been studied in clinical trials, the use of Seroquel® Prolong 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 unwanted 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:

Seroquel® Prolong should be taken once a day on an empty stomach (at least one hour before meals). Tablets must be swallowed whole - do not share, do not chew and do not break.

Adults

Treatment of schizophrenia, moderate and severe manic episodes in the structure of bipolar disorder

Seroquel® Prolong should be taken at least 1 hour before meals.

The daily dose for the first 2 days of therapy 1 day - 300 mg, the 2nd day - 600 mg. The recommended daily dose is 600 mg, but if necessary, it can be increased to 800 mg / day. Depending on the clinical effect and individual patient tolerance, the dose can vary from 400 to 800 mg / day. For maintenance therapy in schizophrenia, there is no need to adjust the dose after relieving the exacerbation.

Treatment of episodes of depression in the structure of bipolar disorder

Seroquel® Prolong should be taken before bedtime. 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 daily dose is 300 mg. Depending on the clinical effect and individual patient tolerance, the dose can be increased to 600 mg. The advantages of using Seroquel® Prolong in a daily dose of 600 mg compared to 300 mg were not detected. Seroquel® Prolong in a dose exceeding 300 mg should be prescribed by a physician with experience in the therapy of bipolar disorders.

Prevention of recurrence of bipolar disorder in patients with prior effective quetiapine therapy of manic or depressive episodes in the structure of bipolar disorder

To prevent recurrence of manic, depressive and mixed episodes in bipolar disorders, patients with a positive response to treatment with Seroquel® Prolong should continue therapy at the same daily dose as at the beginning of therapy.

Seroquel® Prolong should be taken before bedtime. Depending on the clinical effect and individual patient tolerance, the dose may vary from 300 to 800 mg / day. For maintenance therapy, the minimum effective dose of Seroquel® Prolong is recommended.

Combination therapy of a depressive episode with a suboptimal response to antidepressant monotherapy

Seroquel® Prolong should be taken before bedtime. A minimum effective dose should be used, starting therapy with 50 mg / day. The daily dose is: 1st and 2nd day - 50 mg, 3-and 4-day - 150 mg. An increase in the dose from 150 mg / day to 300 mg / day should be based on an individual assessment of the patient's condition. When using high doses of the drug, the risk of side effects increases.

Translation from the administration of Seroquel® to Seroquel® Prolong

For convenience of reception, patients currently receiving fractional therapy with Seroquel® can be transferred to receive Seroquel® Prolong once a day at a dose equivalent to the total daily dose of Seroquel®. In some cases, a dose adjustment may be necessary.

Elderly patients

As with other antipsychotics, Seroquel® Prolong should be used with caution in elderly patients, especially at the beginning of therapy. Selection of an effective dose of Seroquel® Prolong in elderly patients may be slower, and the daily therapeutic dose is lower than in young patients. The average plasma clearance of quetiapine in elderly patients is 30-50% lower than in young patients. In elderly patients, the initial dose of Seroquel® Prolong is 50 mg / day. The dose can be increased by 50 mg / day to an effective dose, depending on the clinical response and the tolerance of the drug to the individual patient.

In elderly patients with a depressive episode, the daily dose for the first 3 days of therapy is 50 mg / day with an increase to 100 mg / day on the 4th day and up to 150 mg / day on the 8th day.Use the minimum effective dose of the drug, starting treatment with 50 mg / day. If necessary, the dose of the drug can be increased to 300 mg / day, but not earlier than 22 days of therapy.

Patients with renal insufficiency

For patients with renal insufficiency, dose adjustment is not required.

Patients with hepatic insufficiency

Quetiapine is extensively metabolized in the liver. Therefore, use caution when using Seroquel® Prolong in patients with hepatic insufficiency, especially at the beginning of therapy. It is recommended to start therapy Seroquel® Prolong with a dose of 50 mg / day and increase the dose daily by 50 mg until an effective dose is reached.

Side effects:

Against the background of taking quetiapine, as well as other neuroleptics, it is possible to increase body weight, the emergence of syncope, malignant neuroleptic syndrome, leukopenia, neutropenia and peripheral edema.

The most frequent adverse reactions of quetiapine (> 10%) are drowsiness, dizziness, headache, 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) cholesterol, an increase in body weight and a decrease in hemoglobin concentration. The frequency of unwanted reactions is given in the form of 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.

On the part of the hematopoiesis system
Often	Reduction of hemoglobin concentration²³
Often	leukopenia^1,25 , decrease in the number of neutrophils^1,22 , an increase in the number of eosinophils²⁴
Infrequently	thrombocytopenia, a decrease in the number of platelets¹⁴
Rarely	agranulocytosis²⁷
Frequency unknown	neutropenia¹
From the immune system
Infrequently	hypersensitivity reactions
Rarely	anaphylactic reactions⁶
From the endocrine system
Often	increased serum prolactin concentration^16;a decrease in the concentration of total and free T₄²⁰, decrease in the total T3 concentration²⁰, increased concentration of TSH²⁰
Infrequently	decrease in the concentration of free T₃²⁰
Rarely	syndrome of inadequate secretion of antidiuretic hormone
Metabolic disorders
Often	increased serum triglyceride concentration^1,11, total cholesterol (mainly LDL cholesterol)^1,12, a decrease in the concentration of HDL cholesterol^1,18, weight gain⁹
Often	hyperglycemia^1,7, increased appetite
Infrequently	hyponatremia²⁹, diabetes^1,5,6
Mental disorders
Often	unusual and nightmarish dreams, suicidal thoughts and behavior¹
Rarely	somnambulism and similar phenomena
From the nervous system
Often	dizziness^1,14,17, drowsiness^2,17, headache
Often	dysarthria, fainting^1,14,17, extrapyramidal symptoms^1,13
Infrequently	convulsions¹, restless legs syndrome, tardive dyskinesia^1,6
Cardiac disorders
Often	tachycardia^1,4heart palpitations¹⁹
Infrequently	bradycardia²⁶, lengthening the interval QT^1,13
From the side of the organ of vision
Often	blurred vision
From the side of the vascular system
Often	orthostatic hypotension^1,4,17
Rarely	venous thromboembolism¹
From the respiratory system
Often	dyspnea¹⁹, rhinitis
From the gastrointestinal tract
Often	dry mouth
Often	constipation, indigestion, vomiting²¹
Infrequently	dysphagia^1,8
Rarely	intestinal obstruction / ileus, pancreatitis
From the liver and biliary tract
Often	increased ALT and AST activity in blood serum³, increased serum GGT activity³
Rarely	jaundice⁶, hepatitis⁶
From the side of the kidneys and urinary tract
Infrequently	retention of urine
From the skin and subcutaneous tissues
Rarely	angioedema⁶, Stevens-Johnson syndrome⁶
From the musculoskeletal and connective tissue
Rarely	rhabdomyolysis
Pregnancy, postpartum and perinatal conditions
Unspecified frequency	withdrawal syndrome in newborns²⁸
From the side of the reproductive system
Infrequently	sexual dysfunction
Rarely	priapism, galactorrhea, menstrual cycle disorders
General disorders
Often	withdrawal syndrome^1,10
Often	slightly expressed asthenia, irritability, peripheral edema, fever
Rarely	malignant neuroleptic syndrome¹
Changes in laboratory and instrumental indicators
Rarely	increased activity of creatine phosphokinase in the blood¹⁵

1. See section "Special instructions"

2. Drowsiness usually occurs within the first 2 weeks after initiation of therapy and is usually resolved against the background of continued use of quetiapine.

3. Perhaps an asymptomatic increase (≥ 3 times the upper limit of the norm when measured at any time), the activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) in blood plasma is generally reversible against the background of continued use of quetiapine.

4. Like other antipsychotics with α₁adrenoblocking 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 research.

7. Increased fasting blood glucose ≥ 126 mg / dl (≥ 7.0 mmol / L) or blood glucose after meals ≥ 200 mg / dL (≥ 11,1 mmol / l), at least for a single determination.

8. A higher incidence of dysphagia with 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 studies 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 quetiapine was discontinued.

11. Increase in the concentration of triglycerides ≥ 200 mg / dl (≥ 2.258 mmol / L) in patients ≥ 18 years or 150 mg / dl (≥ 1.694 mmol / l) in patients <18 years of age, at least once.

12. Increase in total cholesterol concentration ≥ 240 mg / dl (≥ 6.2064 mmol / L) in patients older than 18 years of age or ≥ 200 mg / dl (≥ 5.172 mmol / L) in patients <18 years of age, at least once. Very often increased LDL cholesterol ≥30 mg / dl (≥0.769 mmol / l), an average of 41.7 mg / dl (≥1.07 mmol / l).

13. See further in the text of the Instruction.

14. Decreased platelet count ≤ 100 x 10⁹at least once.

15. Without communication with a malignant neuroleptic syndrome. According to clinical studies.

16. Increase in prolactin concentration in patients ≥ 18 years: ≥ 20 μg / l (≥ 869.56 pmol / L) in men; ≥ 30 μg / l (≥ 1304.34 pmol / L) in women.

17. Can lead to a fall.

18. Reducing the concentration of HDL cholesterol <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 the total T₄, free T₄, the total T₃, free T₃ to values <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 old).

22. In short-term clinical trials of monotherapy with quetiapine in patients with neutrophil count before initiating 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. Decreased neutrophil count ≥ 0.5 x 10⁹/ l, 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 at least for a single determination was observed in 0.21% of patients in the quetiapine group against 0% in the placebo group.

23. Reduction of hemoglobin concentration ≤ 13 g / dl for men and ≤ 12 g / dl in women, at least once, was noted in 11% of patients on quetiapine in all clinical trials, including long-term therapy. In short-term placebo-controlled studies, a decrease in hemoglobin concentration <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 with 6.2% in the placebo group.

24. Na the basis of potentially clinically significant deviations from the baseline normal level, noted in all clinical studies. Increase in the number of eosinophils ≥ 1 x 10⁹/ l when measured at any time.

25. Based on potentially clinically significant deviations from the baseline normal level noted in all clinical trials. Reducing the number of leukocytes ≤ 3x10⁹/ l when measured at any time.

26. It can develop at the time or after the start of therapy and is 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 estimate in patients who participated in all clinical studies of quetiapine who had severe neutropenia (<0.5 x 10⁹/ l) in combination with infections.

28. See "Application during pregnancy and during breastfeeding".

29. The change in concentration from> 132 mmol / l to <132 mmol / l at least once.

30. Interval frequency QTc from <450 msec to ≥ 450 msec with an increase of ≥ 30 ms. In placebo-controlled studies, the number of patients who had a clinically significant increase in the interval QTc, was similar in quetiapine and placebo groups.

Interval lengthening QT, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered side effects of neuroleptics.

Children and adolescents (aged 10 to 17 years)

Children and adolescents may develop the same unwanted reactions as in adult patients. The table shows undesirable reactions that were not observed in adult patients, or more often in children and adolescents (aged 10-17 years) compared with adult patients.

The frequency of unwanted reactions is given in the form of 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.

Metabolic disorders
Often	increased appetite
Changes in laboratory and instrumental indicators
Often	increased serum prolactin concentration¹, increased blood pressure²
Rarely	somnambulism and similar phenomena
From the nervous system
Often	fainting
From the respiratory system
Often	rhinitis
From the gastrointestinal tract
Often	vomiting

1. Increased prolactin concentration in patients <18 years of age:> 20 μg / L (> 869.56 pmol / L) in male patients; > 26 mcg / l (> 1130.43 pmol / L) in female patients. Less than 1% of patients had an increase in prolactin concentration> 100 μg / l (4347.8 pmol / l).

2. Increase in blood pressure above the clinically significant threshold (adapted by the criteria of the National Health Institute, USA - National Health Institute) or increase by more than 20 mm Hg. Art. for systolic or more than 10 mm Hg. Art. for diastolic pressure according to two short-term (3-6 weeks) placebo-controlled studies in children and adolescents.

Overdose:

A lethal outcome was reported when 13.6 g quetiapine was taken from a patient who participated in a clinical trial and also a lethal outcome after taking 6 g quetiapine for 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 that resulted in lengthening of the QTC interval, death or coma.

In patients with severe cardiovascular disease, the risk of developing unwanted reactions in case of an overdose may increase (see section "Special instructions").

Symptoms, noted in overdose, were mainly due to the enhancement of known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and lowering blood pressure. There are also reports of single cases of Seroquel® Prolong overdose that led to rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and agitation.

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.

In case of occurrence of refractory arterial hypotension in case of quetiapine overdose treatment should be performed by intravenous fluid and / or sympathomimetic drugs (should not be prescribed epinephrine and dopamine, since stimulation ββ-adrenoreceptors may cause an increase in blood pressure lowering with the blockade of α-adrenergic receptors with quetiapine). Gastric lavage (after intubation, if the patient is unconscious) and the use of activated charcoal and laxatives can promote the removal of unabsorbed quetiapine, but 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, the combined use of quetiapine (25 mg) with ketoconazole, an inhibitor of isozyme CYP3A4, resulted in an increase in the area under the curve "concentration - time" (AUC) of quetiapine 5-8 times. Therefore, the combined use of quetiapine and inhibitors of the isoenzyme CYP3A4 is contraindicated. When quetiapine therapy is not recommended to eat grapefruit juice.

The pharmacokinetic study quetiapine in varying doses prior to or simultaneously with carbamazepine resulted in a significant increase in clearance of quetiapine and, accordingly, decrease AUC, on average, by 13%, compared with the reception of quetiapine 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 quetiapine therapy.

The combined use of quetiapine with phenytoin, another inducer of microsomal liver enzymes, was accompanied by an even more pronounced (about 450%) increase in quetiapine clearance.

The use of quetiapine by patients receiving inducers of microsomal liver enzymes,is possible only if the expected benefit from quetiapine therapy is greater than 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 quetiapine and thioridazine led to an increase in the 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 the simultaneous use of quetiapine. There were no clinically significant changes in the pharmacokinetics of valproic acid and quetiapine when co-administered semiotric and quetiapine valproate.

With the simultaneous use of quetiapine with lithium in adult patients with acute manic episodes, a higher incidence of adverse reactions associated with EPS (especially tremor), drowsiness and weight gain was noted compared with patients taking quetiapine with a placebo in a 6-week randomized trial.

Pharmacokinetic studies on the interaction of the drug Seroquel® Prolong with drugs used in cardiovascular diseases have not been conducted.

Caution should be exercised in the combined use of quetiapine and drugs that can cause electrolyte imbalance and prolongation of the QT interval_C.

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® Prolong 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, some adverse reactions (increased appetite, increased concentration of prolactin in the blood serum, and ESR) in children and adolescents were observed more frequently than in adults. 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 is associated with an increased risk of suicidal thoughts, self-harm and suicide (events associated with 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.

According to data from short-term placebo-controlled clinical trials 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 aged> 25 years.

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.

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 aged> 25 years; 1.0% (2/193) for quetiapine and 0% (0/90) for placebo in patients under the age of 18 years.

In patients with schizophrenia, 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 aged> 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 a depressive episode, the risk of suicidal events was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo in patients aged 18-24 years; 0.6% (11/1798) for quetiapine and 0.7% (7/1054) for placebo for patients aged> 25 years. Patients under the age of 18 years in the studies on this indication did not participate.

In general, 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).

A meta-analysis of placebo-controlled studies of antidepressants conducted by the FDA (the Food and Drug Administration, USA), summarizing data from approximately 4,400 children and adolescents and 7,700 adult patients with mental disorders, revealed an increased risk of suicidal behavior compared with placebo in antidepressant medications children, adolescents and adult patients under the age of 25 years. This meta-analysis does not include studies where it was used quetiapine (see the section "Pharmacodynamics").

Extrapyramidal symptoms

An increase in the incidence of EPS when taking quetiapine in adults with a large depressive episode instructure of bipolar disorder or major depressive disorder compared with placebo (see section "Side effect"). However, when quetiapine treatment of patients with schizophrenia and mania in the structure of bipolar disorder did not reveal an increase in the incidence of EPS in comparison with placebo.

Late dyskinesia

Against the background of taking antipsychotics, including quetiapine, tardive dyskinesia may occur, which is manifested by violent involuntary movements and may be irreversible. In the case of the development of symptoms of tardive dyskinesia, it is recommended to reduce the dose of the drug or gradually cancel it. Symptoms of tardive dyskinesia may increase or even occur after discontinuation of the drug (see the "Side effect" section).

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.

Drowsiness and dizziness

During therapy with quetiapine, drowsiness and related symptoms, for example sedation (see "Side effect"), may be noted. In clinical studies involving patients with depression in the structure of bipolar disorder and with a depressive episode, drowsiness has generally developed during the first three days of therapy.

The severity of this undesirable reaction was mostly mild or moderate. With the development of severe drowsiness, patients with depression in the structure of bipolar disorder and patients with a depressive episode 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 quetiapine therapy may be discontinued.

On the background of quetiapine therapy, orthostatic hypotension and dizziness may occur (see the "Side effect" section), usually during dose selection at the beginning of therapy. Patients, especially the elderly, should be careful to avoid accidental injuries (falls).

Patients with cardiovascular diseases

Caution should be exercised in appointing quetiapine to patients with cardiovascular and cerebrovascular diseases, and other conditions predisposing to hypotension. In such patients, dose selection should be slower. On the background of quetiapine therapy, orthostatic hypotension may occur, especially during dose selection at the beginning of therapy. When orthostatic hypotension occurs, a dose reduction or more gradual selection 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").

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, quetiapine should be withdrawn and treated accordingly.

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 post-registration (including fatal). Most of these cases of severe neutropenia occurred several months after initiation of quetiapine therapy. There was no dose-response 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 white blood cell count and cases of drug-induced neutropenia in the anamnesis. 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 control the number of neutrophils (before increasing their content to 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 the plasma and can reduce the effectiveness of therapy with the drug Seroquel® Prolong. The appointment of Seroquel® Prolong to patients receiving inductors of microsomal liver enzymes is possible only if the expected benefit of Seroquel® Prolong therapy exceeds the risk associated with cancellation of the inducers 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).

Body mass

Against the background of taking quetiapine, there was an increase in body weight. Clinical observation of patients in accordance with established standards of therapy is recommended (see section "Side effect").

Hyperglycaemia

Against the background of taking quetiapine may develop hyperglycemia and / or the development and exacerbation of diabetes, sometimes accompanied by ketoacidosis or coma. It is recommended to regularly monitor body weight and symptoms of hyperglycemia, such as polydipsia, polyuria, polyphagia and weakness, in patients taking antipsychotics, including quetiapine. Clinical observation of patients with diabetes mellitus, patients with risk factors for the development of diabetes mellitus is recommended (see the "Side effect" section).

Concentration of lipids

Against the background of taking quetiapine may increase the concentration of triglycerides, total cholesterol and LDL cholesterol, as well as a decrease in the concentration of HDL in the blood (see.section "Side effect").

The specified changes should be corrected according to the current recommendations.

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 prolongation There was no correlation between the use of quetiapine and the steady increase in the absolute value of the QT interval. However, 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 diseases and with prolongation of the QT interval in the anamnesis. Care should also be taken when administering quetiapine concomitantly with QTC-prolonging drugs, other antipsychotics, especially in the elderly, in patients with congenital QT prolongation syndrome, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia.section "Interaction with other drugs and other forms of interaction").

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® Prolong 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® Prolong should be used with caution in patients at risk of stroke.

Analysis of the use of atypical antipsychotics for the treatment of psychoses associated with dementia in elderly patients revealed an increase in mortality in the group of patients receiving drugs of this group, compared with the placebo group.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 mortality 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

If jaundice develops, quetiapine 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. Before and during therapy with antipsychotic drugs, including quetiapine, risk factors should be assessed and preventative measures taken.

Pancreatitis

During clinical trials and post-registration use, cases of pancreatitis have been noted, but a causal relationship with the drug has not been established. Post-registration reports indicate that many patients were at risk for developing pancreatitis, such as increased triglyceride concentrations (see subsection Lipid Concentration), cholelithiasis and alcohol use.

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.

Cardiomyopathy and myocarditis

During clinical trials and post-registration 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.Additional information The long-term safety and efficacy of Seroquel® Prolong as an adjunctive therapy for the treatment of major depressive disorder have not been studied, but the safety and efficacy profile has been studied with monotherapy.

Effect on the ability to drive transp. cf. and fur:

Seroquel® Prolonging can cause drowsiness, therefore, during the treatment period, it is not recommended for patients to work with mechanisms that are dangerous, including vehicle management is not recommended.

Form release / dosage:

The tablets of the prolonged action, covered with a film membrane, on 50 mg, 150 mg, 200 mg, 300 mg and 400 mg.

Packaging:

For 10 tablets in Al / PVC blister, 6 blisters each with instructions for use in a cardboard pack with the control of the first autopsy.

When packing at ZiO-ZAO CJSC, Russia:

For 10 tablets in Al / PVC blister, 6 blisters each in a cardboard box with instructions for use.

For 10 tablets in Al / PVC blister, 6 blisters each with instructions for use in a cardboard pack with the control of the first autopsy.

Storage conditions:

Store at a temperature not exceeding 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:LSR-006700/10

Date of registration:15.07.2010

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: & nbsp09.09.2014

Illustrated instructions

Instructions

Seroquel® Prolong (SEROQUEL® PROLONG)