Quetiapine Canon Prolong - instructions for use, dose, side effects, contraindications

Excipients: hypromellose (hydroxypropylmethylcellulose) 156 mg, lactose monohydrate 56.75 mg, magnesium stearate 7.8 mg, sodium citrate 70.01 mg, microcrystalline cellulose 56.75 mg.

Composition of the film shell: Opadry II blue 16 mg, including: polyvinyl alcohol 6.4 mg, macrogol (polyethylene glycol) 3.232 mg, talc 2.368 mg, titanium dioxide 3.28 mg, indigo carmine dye 0.688 mg, red dye red 0.032 mg.

Dosage 200 mg

1 tablet of prolonged action, film-coated, contains:

Active substance: quetiapine fumarate (quetiapine hemifumarate) 230.26 mg, calculated on quetiapine 200 mg.

Excipients: hypromellose (hydroxypropylmethylcellulose) 180 mg, lactose monohydrate 52.87 mg, magnesium stearate 9 mg, sodium citrate 75 mg,cellulose microcrystalline 52.87 mg.

Composition of the film shell: Opadrai II blue 18 mg, including: polyvinyl alcohol 7.2 mg, macrogol (polyethylene glycol) 3.636 mg, talc 2.664 mg, titanium dioxide 3.69 mg, indigo carmine dye 0.774 mg, red dye red 0.036 mg.

Dosage of 300 mg

1 tablet of prolonged action, film-coated, contains:

Active substance: quetiapine fumarate (quetiapine hemifumarate) 345.38 mg, calculated on quetiapine 300 mg.

Excipients: hypromellose (hydroxypropylmethylcellulose) 225 mg, lactose monohydrate 38.06 mg, magnesium stearate 13.5 mg, sodium citrate 90 mg, microcrystalline cellulose 38.06 mg.

Composition of the film shell: Opadrai II blue 23 mg, including: polyvinyl alcohol 9.2 mg, macrogol (polyethylene glycol) 4.644 mg, talc 3.404 mg, titanium dioxide 4.715 mg, indigo carmine dye 0.989 mg, red dye red 0.046 mg.

Dosage of 400 mg

1 tablet of prolonged action, film-coated, contains:

Active substance: quetiapine fumarate (quetiapine hemifumarate) 460.51 mg, calculated on quetiapine 400 mg.

Excipients: hypromellose (hydroxypropylmethylcellulose) 270 mg, lactose monohydrate 26.74 mg, magnesium stearate 16.01 mg,sodium citrate 100 mg, microcrystalline cellulose 26.74 mg.

Composition of the film shell: Opadry II blue 28 mg, including: polyvinyl alcohol 11.20 mg, macrogol (polyethylene glycol) 5.666 mg, talc 4, 144 mg, titanium dioxide 5.74 mg, indigo carmine dye 1.204 mg, red dye red 0.056 mg.

Description:

Tablets are round, biconcave (dosages of 150 mg and 200 mg); tablets are oval, biconcave (dosages of 300 mg and 400 mg), covered with a film shell of blue color. On the cross-section - the core is almost white.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.04 Quetiapine

Pharmacodynamics:

Quetiapine is an atypical antipsychotic. Quetiapine and its active metabolite N-desalkylkvetiapine (norkvetiapin) interact with a wide range of neurotransmitter receptors in the brain. Quetiapine and N-desalkylketiapine show a high affinity for 5HT₂-serotonin receptors and D₁ and D₂dopamine receptors of the brain. Antagonism to these receptors in combination with a higher selectivity to 5HT₂serotonin receptors than to D₂dopamine receptors, determines the clinical antipsychotic properties of the preparation Quetiapine Canon Prolong and the low frequency of extrapyramidal undesirable reactions. Quetiapine has no affinity for the carrier of norepinephrine and has a low affinity for 5HT_1Aserotonin receptors, while N-dealkylketiapine exhibits a high affinity for them. Inhibition of norepinephrine and partial agonism with 5HT_1A - serotonin receptors, manifested N-dealkylkvetiapine, can cause antidepressant effect of the drug Quetiapine Canon Prolong.

Quetiapine and N-dealkalketiapine have a high affinity for histamine and α₁-adrenoceptors 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-dealkylkvetiapa 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-nigrosgriate 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 major depressive disorder quetiapine in doses from 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 the symptoms of depression on a scale MADRS (Montgomery-Asberg Depression Rating Scale, The Montgomery-Asberg Depression Rating Scale) (mean square change of 7.54) compared with placebo. With the exception of the frequency of EPS, the tolerability of quetiapine 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 quetiapine.

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

In two short-term (6-week) studies of combined therapy for a depressive episode quetiapine at a dose of 150 mg / succulent and 300 mg / day with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, or venlafaxine in patients with a suboptimal response to antidepressant monotherapy, an improvement in depressive symptoms 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 intake of food does not significantly affect the bioavailability of quetiapine.

Distribution

Quetiapine is approximately 83% bound to plasma proteins. The pharmacokinetics of quetiapine and N-dealkylkvetiapine is linear, the difference between men and women is not observed.

The maximum concentration of quetiapine and N-dealkylkvetiapine in blood plasma is achieved approximately 6 hours after taking the drug. The equilibrium molar concentration of the active metabolite of N-desalkylkvetiapine is 35% of that of quetiapine.

Metabolism

Quetiapine is actively metabolized in the liver. 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 10-50 times higher than the concentrations observed at the usual effective dose of 300-450 mg / day.

According to a study of interactions in healthy volunteers, concomitant use of quetiapine (at a dose of 25 mg) and ketoconazole (an inhibitor CYP3A4) caused a 5-8 fold increase in the indicator AUC quetiapine. Based on these data, simultaneous use of quetiapine with inhibitors CYP3A4 is contraindicated.

The main metabolites in the blood plasma do not have a pronounced pharmacological activity.

When taking quetiapine once a day at a dose equivalent to the daily dose of the drug taken in two doses, similar areas were observed under the concentration versus time curvesAUC), but the maximum concentration in the plasma (C_mOh) was 13% less. Value AUC metabolite N-dealkylketipipa was 18% less.

Excretion

The half-life (T_1/2) quetiapine is about 7 hours. On average, less than 5% of the molar dose of the fraction of free quetiapine and N-descalklykvetiapine plasma are 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 intestines.

Pharmacokinetics in special cases

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) and in patients with hepatic insufficiency (compensated alcoholic cirrhosis), but individual clearance rates are within the values found in healthy volunteers.

Quetiapine is extensively metabolized in the liver, in patients with hepatic insufficiency, an increase in the plasma concentration of quetiapine is possible, which requires dose adjustment.

Indications:

- Treatment of schizophrenia;

- Treatment of bipolar disorder, including:

Moderate and severe manic episodes in the structure of bipolar disorder;
Severe episodes of depression in the structure of bipolar disorder.

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 HIV protease inhibitors (see "Interactions with Other Drugs and Other Interactions");

- Age up to 18 lay down (efficacy and safety not established);

- Psychoses in elderly patients (over 65 years) suffering from dementia;

- Pregnancy and the period of breastfeeding.

Carefully:

In patients with cardiovascular and cerebrovascular diseases or other conditions,predisposing to arterial hypotension; simultaneous use with drugs that increase the interval QT (including neuroleptics), especially in elderly patients, in patients with congenital syndrome of lengthening the interval QT, congestive heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia; combination with drugs that have an inhibitory effect on the central nervous system (CNS) or alcohol; hepatic failure, convulsive fits in the anamnesis; patients with risk factors for stroke; patients with risk of developing 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:

Quetiapine Kanon 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

The drug Quetiapine Canon Prolong 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 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 bipolar disorder including: moderate and severe manic episodes in the structure of bipolar pasnappyctata; severe episodes of depression in the structure of bipolar passtryystva

Quetiapine canon 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. Advantages of using the drug Quetiapine Kanon Prolong in a daily dose of 600 mg compared with 300 mg was not detected. Quetiapine Kanon Prolong in a dose exceeding 300 mg should be prescribed by a physician with experience in the therapy of bipolar disorders.

Transfer from drug administration Quetiapine for the drug Quetiapine Canon Prolong

For convenience of admission, patients currently receiving fractional drug therapy Quetiapine, can be transferred to receive the drug Quetiapine Canon Prolong once a day at a dose equivalent to the total daily dose of the drug Quetiapine. In some cases, a dose adjustment may be necessary.

Elderly patients

Also, like other antipsychotics, Quetiapine Canon Prolong should be used with caution in elderly patients, especially at the beginning of therapy. Selection of an effective dose of the drug Quetiapine Canon Prolong in the elderly 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 Quetiapine Canon 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, caution should be exercised when using Quetiapine Canon Prolong in patients with hepatic impairment, especially at the onset of therapy. It is recommended to begin therapy drug Quetiapine Canon Prolong a dose of 50 mg / day and to increase the daily dose by 50 mg to achieve an effective dose.

Side effects:

Against the background of taking quetiapine. like other antipsychotics, may increase body weight, the occurrence of syncope, neuroleptic malignant syndrome, leucopenia, neutropenia and peripheral edema.

The most frequent adverse reactions quetiapine (≥10%) - drowsiness, dizziness, headache, dry mouth syndrome "cancel", increasing the concentration of triglycerides, increased total cholesterol concentration of low density lipoproteins - LDL) lowering the concentration of high density lipoprotein cholesterol (HDL ), 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 (from ≥1 / 100 to <1/10),

infrequently (from ≥ 1/1000 to <1/100),

rarely (from≥1 / 10,000 to <1/1000),

very rarely (<1/10000),

unspecified frequencies.

On the part of the hematopoiesis system
Often	Reduction of hemoglobin concentration²³
Often	Leukopenia¹_’²⁵, decrease in the number of neutrophils ^1,25, an increase in the number of eosinophils²⁴
Infrequently	Thrombocytopenia, decrease in the number of platelets¹⁴
Rarely	Agranulocytosis²⁷
Infrequently	Neutropenia¹
From the immune system
Infrequently	Hypersensitivity reactions
Rarely	Anaphylactic reactions ⁶
From the endocrine system
Often	Increase in the concentration of prolactin in the blood plasma¹⁶, a decrease in the concentration of total and free T4²⁰ in blood plasma, a decrease in the total T3 concentration²⁰ in blood plasma, increased concentration of TSH²⁰ in the blood plasma
Infrequently	Reduction of free T3 concentration in blood plasma²⁰
Rarely	Syndrome of inadequate secretion of antidiuretic hormone
Metabolic disorders
Often	Increase in serum triglyceride concentration^1,11total cholesterol (mainly, LDL cholesterol)^1,12 in the blood, lowering the concentration of HDL cholesterol¹_’¹⁸ in the blood, increase in body weight⁹
Often	Hyperglycaemia¹_’⁷, increased appetite
Infrequently	Hyponagryemia²⁹, 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^1,4,17, drowsiness^2,17 headache
Often	Dysatria, fainting¹_’⁴_’¹⁷, extrapyramidal symptoms^1,13
Infrequently	Convulsions¹, restless legs syndrome, tardive dyskinesia^1,6
Disturbance of cardiac activity
Often	Tachycardia^1,4, a feeling of heartbeat¹⁹
Infrequently	Bradycardia¹⁶, 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 activity of ALT in serum³, increased activity ACT 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	The syndrome of "cancellation" in newborns²⁸
From the side of the reproductive system
Infrequently	Sexual dysfunction
Rarely	Priapism, galactorrhea, menstrual disorders
General disorders
Rarely	The "cancellation" syndrome^1,10
Often	Slightly expressed asthenia, irritability, peripheral edema, fever
Rarely	Malignant neuroleptic syndrome¹, hypothermia
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 backdrop of continued use of quetiapine.

3. Perhaps asymptomatic increase (≥3 times from the upper limit of the norm when determining at any time) activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT) and gamma-glutamyltranspeptidase (GGT) in the blood serum, as a rule, reversible against the background of continued use of quetiapine.

4. Like other antipsychotic drugs with α1-adrenergic blocking 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 exacerbation of diabetes mellitus were noted.

6. The frequency of this undesirable reaction was estimated on the basis of the results of post-registration observation of the use of quetiapine.

7. An increase in fasting blood glucose ≥ 126 mg / dL (≥ 7.0 mmol / L) or postprandial blood glucose ≥ 200 mg / dL (≥ 11.1 mmol / L), at least once.

8. A higher incidence of dysphagia with quetiapine compared with placebo was noted only in patients with depression in the structure of bipolar disorder.

9. An increase in the initial body weight by 7% or more. Basically, it occurs at the beginning of therapy in adults.

10. When studying the syndrome of "withdrawal" in short-term placebo-controlled clinical trials of quetiapine monotherapy regimen, the following symptoms were noted: insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability.The frequency of the "withdrawal" syndrome was significantly reduced 1 week after discontinuation of the drug.

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

12. An increase in the total cholesterol concentration ≥ 240 mg / dL (≥ 6.2064 mmol / L) in patients ≥18 years of age or ≥ 200 mg / dL (≥5, 172 mmol / l) in patients <18 years of age, at least once. Very often an increase in LDL cholesterol was ≥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 19⁹/ l, at least for a single determination.

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

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

17. May lead to a fall.

18. Reduction in HDL cholesterol concentration <40 mg / dl (<1.03 mmol / l) in men and <50 mg / dL (<1.29 mmol / L) in women.

19. These phenomena are often noted against a background of tachycardia, dizziness, orthostatic hypotension and / or concomitant pathology of the cardiovascular or respiratory system.

20. Based on potentially clinically significant deviations from the normal baseline, noted in all clinical studies. Changes in the concentration of total thyroxine (T4), free T4, total triiodothyronine (T3), free T3 to values <80% of the lower limit of the norm (pmol / L) when determined at any time. Change in the concentration of thyroid hormone (TTG)> 5 mIU / l at any time.

21. Based on the increased incidence of vomiting in elderly patients (age ≥ 65 years).

22. In short-term clinical studies of monotherapy with quetiapine in patients with neutrophil count prior to initiation of therapy ≥1.5 x 10⁹/ l cases of neutropenia (number of neutrophils <1.5 x 10⁹/ l) were observed in 1.9% of patients in the quetiapine group versus 1.5% in the placebo group. Decrease in the number of neutrophils ≥0.5, but <1.0 x 10⁹/ l was noted with a frequency of 0.2% in the quetiapine group and placebo. Decrease in the number of neutrophils <0.5 x 10⁹/ l, even for a single determination, 0.21% of patients in the quetiapine group were compared to 0% in the placebo group.

23. Reduction of hemoglobin concentration ≤ 13 g / dl in males and ≤ 12 g / dl in females, at least once, was noted in 11% of patients on quetiapine in all clinical trials, including long-term therapy.T3 short-term placebo-controlled studies showed that 8.3% of patients in the quetiapine group had a reduction in hemoglobin ≤13 g / dL in men and <12 g / dL in women, at least once, compared with 6.2% in the group with placebo.

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

25. The basis for potentially clinically significant deviations from the baseline normal level, noted in all clinical studies. Reducing the number of leukocytes ≤3 x 10⁹/ l when measured at any time.

26. It may develop at or soon after initiation of therapy and be accompanied by arterial hypotension and / or syncope. The frequency is based on reports of bradycardia and related adverse events in all clinical studies of quetiapine.

27. Based on the frequency assessment in patients who participated in all clinical studies of quetiapine who experienced severe neutropenia (≤0.5 × 10⁹ / l) in combination with infections.

28. Cm.section "Application during pregnancy and during breast-feeding".

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

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

Interval lengthening QT, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered undesirable reactions inherent in 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 (from ≥ 1/100 to <1/10),

infrequently (from ≥ 1/1000 to <1/100),

rarely (from ≥ 1/10000 to <1/1000),

very rarely (<1/10000),

frequency, unspecified.

Metabolic disorders
Often	Increased appetite
Change 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]. Increase in prolactin concentration in patients <18 years of age:> 20 μg / L (> 869.56 pmol / L) in male patients; > 26 μg / l (> 1,130.43 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 Institute of Health, USA - National Health Institute) or an increase 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-controllyreresearch 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 leading to lengthening of the interval QT_C, 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 increase in known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and lowering 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 breathing 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 of β-adrenoreceptors can 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 of cytochrome P450 (CYP) 3A4 is the main isoenzyme responsible for the metabolism of quetiapine, carried out through the cytochrome P450 system. In healthy volunteers, co-administration of quetiapine (at a dose of 25 mg) with ketoconazole, an isoenzyme inhibitor CYP3A4, led to an increase in the area under the "concentration-time" curve (AUC) quetiapine 5-8 times. Therefore, the combined use of quetiapine and isoenzyme inhibitors CYP3A4 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 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 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 the simultaneous 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 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 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 quetiapine with drugs used in cardiovascular disease have not been conducted.

Caution should be exercised in the combined use of quetiapine and drugs that can cause electrolyte imbalance and lengthening of the interval QT_from.

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)

The drug Quetiapine Canon 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).

Conducted FDA (Food and Drug Administration, USA), a meta-analysis of placebo-controlled studies of antidepressants, summarizing data from approximately 4,400 children and adolescents and 7,700 adult patients with mental disorders, revealed an increased risk of suicidal behavior against antidepressants compared with placebo in 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 major depressive episode in the structure of bipolar disorder or major depressive disorder compared with placebo has been noted (see "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 the patient 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 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 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 Quetiapine Canon Prolong. Administration of the preparation Quetiapine Canon Prolong to patients receiving inducers of microsomal liver enzymes is possible only if the expected benefit from therapy with Quetiapine Canon ProLong 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

On 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"). 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 lipids in the blood in some patients can lead to a deterioration in the metabolic profile, which requires appropriate monitoring.

Interval lengthening QT

There was no correlation between the use of quetiapine and the steady increase in the absolute value of the interval QT. However, the lengthening of the interval QT was noted during an overdose of the drug (see the section "Overdose"). Caution should be exercised when assigning quetiapine, as well as other antipsychotics, to patients with cardiovascular disease and with lengthening of the interval QT in the anamnesis. Also, care should be taken when administering quetiapine concurrently with drugs that extend the interval QT_C, other neuroleptics, especially in the elderly, in patients with congenital elongation of the OT interval, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see "Interactions with Other Drugs and Other Interactions").

Acute reactions, associated with drug cancellation

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

Quetiapine Kanon 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. Quetiapine Kanon 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; average 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 Quetiapine Canon 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:

Quetiapine canon Prolong can cause dizziness and drowsiness, so during the treatment patients are not recommended to drive vehicles, as well as engage in other activities that require concentration and speed of psychomotor reactions.

Form release / dosage:

Tablets of prolonged action, film-coated, 150 mg, 200 mg, 300 mg or 400 mg.

Packaging:

Tablets with a dosage of 150 mg and 200 mg:

For 10 or 15 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

According to 3, 6 contour cell packs of 10 or 2, 4 contour cell packs of 15 tablets together with the instruction for use are placed in a pack of cardboard.

Tablets with a dosage of 300 mg and 400 mg:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 3, 6 contour packs of 10 tablets together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C, in the manufacturer's packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004104

Date of registration:26.01.2017

Expiration Date:26.01.2022

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Representation: & nbspCANONFARMA PRODUCTION CJSC CANONFARMA PRODUCTION CJSC Russia

Information update date: & nbsp28.02.2017

Illustrated instructions

Instructions

Quetiapin Canon Prolong (Quetiapine Canon Prolong)