Quentiaks SR - instructions for use, dose, side effects, contraindications

for 1 tablet of 150 mg
Core
Active substance:
Quetiapine hemifumarate 172.70 mg, equivalent to quetiapine 150.00 m
Excipients: hypromellose 4000 mPas 31.50 mg, hypromellose 100 mPas 103,50 mg, lactose monohydrate 39.55 mg, microcrystalline cellulose 39.75 mg, sodium hydrogen phosphate dihydrate 56.25 mg, magnesium stearate 6.75 mg

Film sheath: Opadrai II NR white 12.17 mg, iron dye red oxide (E172) 0.08 mg, iron dye oxide yellow (E172) 0.25 mg

Opadrai II HP white contains: polyvinyl alcohol partially hydrolyzed 4.87 mg, titanium dioxide (E171) 3.04 mg, macrogol / PEG 3000 2.46 mg, talc 1.80 mg

for 1 tablet of 200 mg
Core
Active substance:
Quetiapine hemifumarate 230.27 mg, equivalent to quetiapine 200.00 mg
Excipients: hypromellose 4000 mPas 42.00 mg, hypromellose 100 mPas 138.00 mg, lactose monohydrate 52.73 mg, cellulose microcrystalline 53.00 mg, sodium hydrogen phosphate dihydrate 75.00 mg, magnesium stearate 9.00 mg

Film sheath: Opadrai II HP white 16.55 mg, ferric oxide yellow oxide (E172) 0.45 mg

Opaprai II HP White contains: partially hydrolysed polyvinyl alcohol 6.62 mg, titanium dioxide (E171) 4.14 mg, macrogol / PEG 3000 3.34 mg, talc 2.45 mg

for 1 tablet of 300 mg
Core
Active substance:
Quetiapine hemifumarate 345.40 mg, equivalent to quetiapine 300.00 mg
Excipients: hypromellose 4000 mPas 63.00 mg, hypromellose 100 mPas 207.00 mg, lactose monohydrate 79.10 mg, cellulose microcrystalline 79.50 mg, sodium hydrogen phosphate dihydrate 112,50 mg, magnesium stearate 13.50 mg

Film sheath: Opadrai II HP white 24.85 mg, ferric oxide yellow oxide (E172) 0.15 mg

Opaprai II HP white contains: polyvinyl alcohol partially hydrolyzed 9.94 mg, titanium dioxide (El71) 6.21 mg, macrogol / PEG 3000 5.02 mg, talc 3.68 mg

Description:

Tablets of 150 mg:
Round biconvex tablets, covered with a film coat of orange-pink color.
View at the break: rough surface of white or almost white color.

Tablets 200 mg:
Oval biconvex tablets, covered with a film coat of brownish-yellow color.
View at the break: rough surface of white or almost white color.

Tablets 300 mg:
Double-convex capsule capsules coated with a film coating of light yellow color.
View at the break: rough surface of white or almost white color.

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-dealkalketiapine have a high affinity for 5NT₂-serotonin receptors and D_1-, D₂dopamine receptors of the brain. Antagonism to these receptors in combination with a higher selectivity to 5HT₂serotonin receptors than to D₂dopamine receptors, causes the main clinical antipsychotic properties of quetiapine and a low incidence 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-dealkalkvetiapine has a high affinity for them. Inhibition of the norepinephrine transporter and partial agonism in relation to 5NT_1A-serotonin receptors, manifested N-dealkylkvetiapine, may cause antidepressant effect of the drug Quentiaks SR. Quetiapine and N-dealkalketiapine have a high affinity for histamine and α₁adrenoreceptors and moderate affinity for α₂adrenoreceptors. Besides, quetiapine It does not possess or has a low affinity for muscarinic receptors, while N-dealkylketiapine 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-dealkalketiapine in 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.

In a short-term (9-week) study in patients without dementia aged 66 to 89 years (19%Patients who were older than 75 years old) with a large depressive disorder received long-acting quetiapine at doses of 50 mg to 300 mg per day (the dose was selected taking into account the tolerability and clinical response, the average daily dose of the drug was 160 mg) reduced the severity of depressive symptoms on a scale MADRS (Montgomery-Asberg Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale) (mean-square change of 7.54 points) compared with placebo. With the exception of the frequency of EPS, the tolerability of long-acting quetiapine once a day in elderly patients was comparable to that 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 quetiapine sustained release.

In studies of major depressive disorder by criteria DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed.) - Handbook of Diagnosis and Statistics of Mental Disorders, 4th edition) did not observe an increase in the risk of suicidal behavior and suicidal thinking when taking long-acting quetiapine compared with placebo.

In two short-term (6-week) studies of combined treatment of a depressed episode with quetiapine sustained release at a dose of 150 mg / day and 300 mg / day with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine in patients with suboptimal response to monotherapy with antidepressant showed improvement in symptoms of depression on a scale MADRS (mean-square change of 2-3.3 points) compared with antidepressant monotherapy.

Pharmacokinetics:

Suction
Quetiapine is well absorbed from the gastrointestinal tract. The maximum concentration (C_max) quetiapine and N-desalkylkvetiapine in blood plasma is achieved approximately 6 hours after taking quetiapine sustained release. The equilibrium molar concentration of the active metabolite of N-desalkylkvetiapine is 35% of that of quetiapine.

The pharmacokinetics of quetiapine and N-dealkylkvetiapine is linear and is dose-dependent when taking quetiapine sustained release at a dose of up to 800 mg once daily.

When taking quetiapine sustained release 1 time per day in a dose,equivalent daily dose of quick release quetiapine taken in 2 doses, similar areas were observed under the concentration versus time curve (AUC), but FROM_max was 13% less. Value AUC metabolite N-dealkalkvetiapine was 18% less.

Studies of the effect of food intake on the bioavailability of quetiapine have shown that eating high-fat foods results in a statistically significant increase FROM_max and AUC for quetiapine sustained release - approximately 50% and 20%, respectively. Low-fat diet did not have a significant effect on FROM_max and AUC quetiapine. It is recommended to take the drug Quentiaks CP 1 time a day apart from eating.

Distribution
Approximately 83% of quetiapine binds to plasma proteins.

Metabolism
It is established that the isoenzyme CYP3A4 is the key isoenzyme of the metabolism of quetiapine mediated by the cytochrome P450 system. N-dealkylkvetiapine is formed with the participation of the CYP3A4 isoenzyme.

Quetiapine and some of its metabolites (including N-desalkylketiapine) have a weak inhibitory activity in relation to the isoenzymes of the cytochrome P450 1A2, 2C9, 2C19, 2D6 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 research 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 the cytochrome P450 system.

Excretion
The half-life of quetiapine and N-desacilkvetiapine is approximately 7 and 12 hours, respectively. On average, less than 5% of the molar dose of the fraction of free quetiapine and N-desacluciliconetin plasma is excreted by the kidneys. Approximately 73% of quetiapine is excreted by the kidneys and 21% by the intestine. Quetiapine is actively metabolized in the liver, less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or through the intestine.

Pharmacokinetics in different patient groups
Floor
Differences in pharmacokinetic parameters in men and women are not observed.

Elderly patients
The average clearance of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.

Impaired renal function
The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min / 1.73m²), but individual clearance rates are within the values found in healthy volunteers.

Impaired liver function
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:
- prevention of relapses 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 previous effective quetiapine treatment 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.
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
Simultaneous use with cytochrome P450 inhibitors, such as antifungal agents of the azole group, erythromycin, clarithromycin and nefazodone, as well as with protease inhibitors (see section "Interaction with other drugs").

Although the efficacy and safety of quetiapine in children and adolescents aged 10-17 years have been studied in clinical trials, the use of Quentiax® SR in patients under the age of 18 years is not indicated.

Carefully:

Use in patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, use in elderly patients, liver failure, convulsive seizures in history, the risk of stroke and aspiration pneumonia.

Pregnancy and lactation:

Pregnancy
Safety and effectiveness of quetiapine in pregnancy are not established. Because of this, during pregnancy, the drug Quentiaks® CP can be used only if the expected benefit for the mother 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.

Breastfeeding period
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:

Inside, once a day, on an empty stomach (at least 1 hour before meals).
Tablets must be swallowed whole, not divided, not chewed and not broken.

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

The drug Quentiaks ® CP should be taken at least 1 hour before meals. The daily dose for the first 2 days of therapy is: 1st day - 300 mg, 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 may 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

The drug Quentiaks ® SR 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. Advantages of the use of the preparation Quentiaks ® SR in a daily dose of 600 mg in comparison with 300 mg was not revealed. Preparation Quentiaks® SR 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 Quentiax® SR should continue therapy at the same daily dose as at the start of therapy. Preparation Quentiaks® CP 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 Quentiax® CP is recommended.

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

The drug Quentiaks ® SR 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 quetiapine in the form of rapid-release tablets to the preparation of Quentiax® SR

For convenience of reception, patients currently receiving fractional quetiapine therapy in the form of rapid-release tablets can be transferred to receive Quentiax® CP once a day at a dose equivalent to the total daily dose of quetiapine in the form of rapid release tablets. In some cases, a dose adjustment may be necessary.

Elderly patients

Like other neuroleptics, Quentiax® CP should be used with caution in elderly patients, especially at the beginning of therapy. Selection of an effective dose of Quentiax® SR 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 Quentiax® SR is 50 mg / day. The dose can be increased by 50 mg / day until an effective dose is obtained, 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.

Impaired renal function

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

Impaired liver function

Quetiapine is extensively metabolized in the liver. Therefore, caution should be exercised when using Quentiax® CP in patients with hepatic impairment, especially at the onset of therapy. It is recommended to start therapy with Quentiax® SR with a dose of 50 mg / day and increase the dose daily by 50 mg until an effective dose is reached.

Side effects:

The use of quetiapine, as well as other antipsychotics, may be accompanied by weight gain, fainting, malignant neuroleptic syndrome, leukopenia, neutropenia and peripheral edema. The most frequent adverse reactions of quetiapine (≥ 10%) - drowsiness,

dizziness, headache, dryness of the oral mucosa, withdrawal syndrome, increasing triglyceride concentration (TG), increasing the concentration of total cholesterol (mainly low-density lipoprotein cholesterol (LDL)), lowering the concentration of high-density lipoprotein (HDL) cholesterol, an increase in body weight and a decrease in hemoglobin.

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 is unknown (can not be estimated from available data).

Violations of the blood and lymphatic system
Often	decrease in hemoglobin²³
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
Immune system disorders
Infrequently	hypersensitivity reactions
Rarely	anaphylactic reactions⁶
Disorders from the endocrine system
Often	increased serum prolactin concentration¹⁶, a decrease in the concentration of total and free thyroxine (T4)²⁰ in blood plasma, a decrease in the concentration of total triiodothyronine (T3)²⁰, an increase in the thyroid-stimulating hormone (TSH) concentration in the blood plasma
Infrequently	a decrease in the concentration of free TK in the blood plasma²⁰
Rarely	syndrome of inadequate secretion of antidiuretic hormone
Disorders from the metabolism and nutrition
Often	increase in serum TG concentration^1,11, total cholesterol (mainly LDL cholesterol)^1,12, a decrease in the concentration of HDL cholesterol^1,18 in blood plasma, weight gain⁹
Often	hyperglycemia^1,7, increased appetite
Infrequently	hyponatremia²⁹, diabetes^1,5,6
Disorders of the psyche
Often	unusual and nightmarish dreams, suicidal thoughts and behavior¹
Rarely	somnambulism and similar phenomena
Disturbances from the nervous system
Often	dizziness^1,4,17, drowsiness^2,17, headache
Often	dysarthria, fainting^1,4,17, extrapyramidal symptoms^1,13
Infrequently	convulsions¹, restless legs syndrome, tardive dyskinesia^1,6
Disturbances on the part of the organ of sight
Often	blurred vision
Heart Disease
Often	tachycardia^1,4, a feeling of heartbeat¹⁹
Infrequently	bradycardia²⁶, lengthening the interval QT^1,13,30
Vascular disorders
Often	orthostatic hypotension^1,4,17
Rarely	venous thromboembolism¹
Disturbances from the respiratory system, chest and mediastinal organs
Often	dyspnea¹⁹, rhinitis
Disorders from the digestive system
Often	dryness of the oral mucosa
Often	constipation, indigestion, vomiting²¹
Infrequently	dysphagia^1,8
Rarely	intestinal obstruction / ileus, pancreatitis
Disturbances from the liver and bile ducts
Often	Increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltranspeptidase (GGT) in serum³
Rarely	jaundice⁶, hepatitis⁶
Disorders from the kidneys and urinary tract
Infrequently	retention of urine
disorders of the skin and subcutaneous tissue
rarely	angioedema⁶, Stevens-Jonson syndrome⁶
disorders of the musculoskeletal and connective tissue
rarely	rhabdomyolysis
pregnancy, postpartum and perinatal conditions
frequency unknown	withdrawal syndrome in newborns²⁸
disorders of the genitals and breast
infrequently	sexual dysfunction
rarely	priapism, galactorrhea, menstrual cycle disorders
General disorders and disorders at the site of administration
Often	withdrawal syndrome^1,10
often	slightly expressed asthenia, irritability, peripheral edema, fever
rarely	malignant neuroleptic syndrome¹, hypothermia
laboratory and instrumental data
rarely	increased activity of creatine phosphokinase in blood plasma¹⁵

see "special instructions".
Drowsiness usually occurs within the first 2 weeks after initiation of therapy and is usually resolved against the backdrop of continued use of quetiapine.
possibly asymptomatic increase (≥ 3 times from the upper limit of the norm when determined at any time), the act, alt and gent activity in the blood serum is usually reversible against the background of the continued use of quetiapine.
as well as other antipsychotic drugs 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").
marked very rare cases of exacerbation of diabetes.
the frequency of this undesirable reaction was estimated on the basis of the results of post-registration observation of the use of quetiapine.
increased fasting plasma glucose ≥ 126 mg / dl (≥ 7.0 mmol / L) or post-prandial plasma glucose ≥ 200 mg / dl (≥ 11.1 mmol / l), at least once.
the higher incidence of dysphagia in quetiapine compared with placebo was noted only in patients with depression in the structure of bipolar disorder.
increase in the initial body weight by 7% or more. mainly occurs at the beginning of therapy in adults.
when 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 "cancellation" syndrome was significantly reduced 1 week after quetiapine was discontinued.
increase in the concentration of n ≥ 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.
increase in the concentration of total cholesterol ≥ 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. increased cholesterol ≥ 30 mg / dl (≥ 0.769 mmol / L), an average of 41.7 mg / dl (≥ 1.07 mmol / L).
see further in the text of the instruction.
decrease in the number of platelets ≤ 100 x 10⁹/ l, at least for a single determination.
without connection with a malignant neuroleptic syndrome. according to clinical studies.
increase in prolactin concentration in patients ≥ 18 years: 20 mcg / l (≥ 869.56 pmol / L) in men,> 30 μg / l (≥ 1304.34 pmol / L) in women.
can lead to a fall.
a decrease in the concentration of LDL cholesterol <40 mg / dL (<1.03 mmol / l) in men and <50 mg / dl (<1.29 mmol / L) in women.
these phenomena are often noted against a background of tachycardia, dizziness, orthostatic hypotension and / or concomitant pathology of the cardiovascular or respiratory system.
based on the potentially clinically significant deviations from baseline noted in all clinical trials. changes in the concentration of total m4, free T4, total T3, free T3 to values <80% of the lower limit of the norm (pmol / L) when determined at any time.a change in the concentration of min> 5 m / d when determined at any time.
on the basis of increased frequency of vomiting in elderly patients (≥ 65 years old).
in short-term clinical trials of quetiapine monotherapy 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. decrease in the number of neutrophils ≥ 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, even for a single determination, 0.21% of patients in the quetiapine group were compared to 0% in the placebo group.
decrease in hemoglobin ≤ 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 ≤ 13 g / dl for 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.
on 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 determined at any time.
on the basis of potentially clinically significant deviations from the baseline normal level, noted in all clinical studies. decrease in the number of leukocytes ≤ 3 x 10⁹/ l when determined at any time.
may develop at or soon after initiation of therapy and be accompanied by arterial hypotension and / or syncope. frequency is based on reports of bradycardia and related adverse events in all clinical studies of quetiapine.
on the basis of frequency estimates in patients who participated in all clinical studies of quetiapine who had severe neutropenia (<0.5 x 10⁹/ l) in combination with infections.
see section "use during pregnancy and during breastfeeding".
a change in the concentration from> 132 mmol / l to <132 mmol / l at least once.
the frequency of the change in the interval qts from <450 msec to ≥ 450 msec with an increase of ≥ 30 ms.in placebo-controlled trials, the number of patients who had a clinically significant increase in the interval of qts was initial in quetiapine and placebo groups.

children and adolescents (aged 10 to 17 years)

In children and adolescents it is possible to develop the same undesirable reactions as in adult patients. in the table there are 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 undesired 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 is unknown (can not be estimated from available data).

metabolic and nutritional disorders
Often	increased appetite
laboratory and instrumental data
Often	increased serum prolactin concentration¹, increased blood pressure²
disorders of the nervous system
often	fainting
disorders of the respiratory system, chest and mediastinal organs
often	rhinitis
disorders of the gastrointestinal tract
Often	vomiting

increase in prolactin concentration in patients <18 years of age:> 20 μg / l (≥ 869.56 pmol / L) in male patients,> 26 μg / L (≥ 1130.43 pmol / L) in female patients. less than 1% of patients showed an increase in the concentration of prolactin> 100 μg / l (4347.8 pmol / l).
increase in blood pressure above the clinically significant threshold (adapted by the criteria of the National Institutes of Health, national health institute) or a rise of 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 with the admission of 13.6 g quetiapine in the patient participating in the clinical study, and also about the fatal outcome after taking 6 g quetiapine in the post-registration study of quetiapine. 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 lengthening of the interval QT_c, death or coma.

In patients with severe cardiovascular disease, the risk of developing side effects with an overdose may increase (see Fig.section "Special instructions").

Symptoms

Symptoms noted in overdose were mainly due to the enhancement of known pharmacological effects of quetiapine, such as drowsiness and sedation, tachycardia and lowering of blood pressure. There are also reports of single cases of quetiapine 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 β-adrenoceptors may cause an increase in blood pressure lowering in the context of blockade αadrenoreceptor 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 while using the drug Quentiax® SR with other drugs that affect the central nervous system, as well as with alcohol.

The cytochrome P450 3A4 isozyme is the main isoenzyme responsible for the metabolism of quetiapine, carried out through the cytochrome P450 system. In healthy volunteers, simultaneous use of quetiapine (at a dose of 25 mg) with ketoconazole, an inhibitor of isoenzyme CYP3A4, led to an increase AUC quetiapine 5-8 times.

Therefore, simultaneous use of quetiapine and isoenzyme inhibitors CYP3A4 it is contraindicated. When quetiapine therapy is not recommended to eat grapefruit juice.

In a pharmacokinetic study, the use of quetiapine in varying dosages prior to or concurrent with carbamazepine administration resulted in a significant increase in quetiapine clearance and, accordingly, a decrease AUC, on average, by 13%, compared with the use of quetiapine without carbamazepine. In some patients, a decrease 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 simultaneous 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 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 the use of an antidepressant imipramine (an inhibitor of the isoenzyme CYP2D6) or fluoxetine (inhibitor of isoenzymes CYP3A4 and CYP2D6).

The pharmacokinetics of quetiapine does not change significantly with simultaneous use 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, while concomitant administration of valproate semetriya and quetiapine.

With simultaneous use of quetiapine with lithium preparations in adults with acute manic episodes, a higher incidence of unwanted 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 Quentiaks ® SR with drugs used in cardiovascular disease have not been conducted.

Caution should be exercised while using 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)

Quentiax® SR 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 unwanted reactions (increased appetite, increased concentration of prolactin in the blood serum and EPS) in children and adolescents observed with a greater frequency,than in adult 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 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 in patients aged ≥ 25 years.

Other psychiatric disorders for which therapy is applied 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 in 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).

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

Extrapyramidal symptoms

An increase in the incidence of EPS when taking quetiapine in adults with a large depressive episode in the structure of bipolar disorder or major depressive disorder compared with placebo was noted (see "Side effect"). However, quetiapine therapy in patients with schizophrenia and mania in the structure of bipolar disorder showed no 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 tended to develop 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 needmore 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 when applying quetiapine in patients with cardiovascular, cerebrovascular diseases and other conditions predisposing to arterial 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 medicines, 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 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 were infrequent (neutrophil count <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 reduced number of leukocytes 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 amount of neutrophils (up to an increase in their number to 1.5 x 10⁹/ l).

Interaction with other drugs

Also see the section "Interaction with other drugs".Simultaneous use of quetiapine with powerful inducers of microsomal liver enzymes, such as carbamazepine and phenytoin, helps to reduce the concentration of quetiapine in the blood plasma and can reduce the effectiveness of therapy with the drug Quentiaks ® SR.

Application of Quentiax® CP in patients receiving inducers of microsomal liver enzymes is possible only if the expected benefit from therapy with Quentiax ® CP surpasses the risk associated with cancellation of 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 quetiapine, an increase in the concentration of triglycerides, total cholesterol and LDL cholesterol, as well as a decrease in the concentration of HDL in the blood plasma (see section "Side effect"). These changes should be adjusted in accordance with the current recommendations.

Metabolic disorders

An increase in body weight, an increase in the concentration of glucose and lipid in the blood plasma 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, prolongation of the QT interval was noted with an overdose of quetiapine (see the section "Overdose").Caution should be exercised when using quetiapine, as well as other antipsychotics, in patients with cardiovascular disease and with a prolonged QT interval in the anamnesis. Also, care should be taken when applying quetiapine simultaneously with drugs that extend the QT interval_c, other neuroleptics, especially in the elderly, in patients with the syndrome of congenital prolongation of the QT interval, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see section "Interaction with other drugs").

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, the cancellation of Quentiax® CP is recommended to be carried out gradually for at least one or two weeks.

Older patients with dementia

Preparation Quentiaks® SR 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. The drug Quentiax® SR 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 the mortality rate 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, caution should be exercised when using Quentiax® CP in 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

Long-term safety and efficacy of Quentiax® SR as an additional therapy for the treatment of major depressive disorder have not been studied, but the safety and efficacy profile has been studied with monotherapy.

Special information on excipients

Preparation Quentiaks® CP contains lactose, so it should not be used in the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

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

The drug Quentiaks SR can cause drowsiness, so during the period of treatment, it is not recommended for patients to work with mechanisms requiring increased concentration of attention, including vehicle control is not recommended.

Form release / dosage:

Tablets of prolonged action, film-coated, 150 mg, 200 mg and 300 mg.

Packaging:

For 10 tablets in a blister of the combined material OPA / Al / PVC and aluminum foil.

By 2, 3, 6, 9 or 10 blisters are placed in a pack of cardboard along with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003528

Date of registration:25.03.2016

Expiration Date:25.03.2021

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, dd, Novo mesto, AO Slovenia

Representation: & nbspKRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Information update date: & nbsp23.08.16

Illustrated instructions

Instructions

Quentiaks® SR (Kventiax® SR)