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

Excipients: cellulose microcrystalline - 8.718 mg, lactose monohydrate - 4,500 mg, sodium carboxymethyl starch (sodium starch glycolate, type A) 3,500 mg, povidone K-30 - 2,000 mg, talc 1.250 mg, silicon dioxide colloid 0.750 mg, magnesium stearate 0.500 mg mg;

film sheath: [hypromellose 0.900 mg, talc 0.3300 mg, titanium dioxide 0.165 mg, macrogol 4000 (polyethylene glycol 4000) 0.135 mg] or [dry mixture for film coating containing hypromellose (60%), talcum powder (20 %), titanium dioxide (11 %), macrogol 4000 (polyethylene glycol 4000) (9%)] - 1,500 mg.

Dosage of 100 mg

active substancesabout: quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 100.0 mg;

Excipients: cellulose microcrystalline - 34.870 mg, lactose monohydrate - 18,000 mg, carboxymethyl starch sodium (sodium starch glycolate, type A) - 14.0 mg, povidone K-30 - 8,000 mg, talc - 5,000 mg, silicon dioxide colloid - 3,000 mg, magnesium stearate - 2,000 mg;

film sheath: [hypromellose - 3,600 mg, talc - 1,200 mg, titanium dioxide - 0,660 mg, macrogol 4000 (polyethylene glycol 4000) - 0,540 mg] or [dry mixture for film coating containing hypromellose (60%), talcum powder (20 %), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 6,000 mg.

Dosage 200 mg

active substance: quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 200.0 mg;

Excipients: cellulose microcrystalline - 69,740 mg, lactose monohydrate 36,000 mg, carboxymethyl starch sodium (sodium starch glycolate, type A) - 28,000 mg, povidone K-30 16,000 mg, talc 10,000 mg, silicon colloidal dioxide 6,000 mg, magnesium stearate 4,000 mg;

film sheath: [hypromellose - 7,200 mg, talc - 2,400 mg, titanium dioxide - 1,320 mg, macrogol 4000 (polyethylene glycol 4000) - 1,080 mg] or [dry mixture for film coating containing hypromellose (60%), talc (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 12,000 mg.

Dosage of 300 mg

active substance: quetiapine fumarate (quetiapine hemifumarate) in terms of quetiapine - 300.0 mg;

Excipients: cellulose microcrystalline - 104,610 mg, lactose monohydrate - 54,000 mg,sodium carboxymethyl starch (sodium starch glycolate, type A) 42.0 mg, povidone K-30 24,000 mg, talc 15,000 mg, silicon colloidal dioxide 9.0 mg, magnesium stearate 6,000 mg;

film sheath: [hypromellose - 10,800 mg, talc - 3,600 mg, titanium dioxide 1,980 mg, macrogol 4000 (polyethylene glycol 4000) 1.620 mg] or [dry mixture for film coating containing hypromellose (60%), talcum powder (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] - 18,000 mg.

Description:

Round biconvex tablets covered with a film coat of white or almost white color. On the cross section, the nucleus is white or almost white in 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 (norkvetiapin) interact with a wide range of neurotransmitter receptors in the brain. Quetiapine and N-dealkylketiapine show a high affinity for 5NT₂-serotonin, 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 quetiapine and the low incidence of extrapyramidal side effects. Quetiapine has no affinity for the carrier of norepinephrine and has a low affinity for 5HT_1Aserotonin receptors, while N-dealkylketiapine shows a high affinity for both. Inhibition of norepinephrine and partial agonism with 5HT_1A-serotonin receptors, manifested N-dealkylkvetiapine, can determine the antidepressant effect of the drug. Quetiapine and N-dealkalketiapine have a high affinity for histamine and α₁adrenoreceptors and moderate affinity for α₂adrenorenoreceptors. 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 quetiapine has antipsychotic activity.

The specific contribution of the metabolite N-dealkylkvetiapine 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 D₂dopamine receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons in comparison with A9 nigrostriate neurons involved in motor function.

Efficiency

Quetiapine is effective against both positive and negative symptoms of schizophrenia.

Quetiapine is effective as a monotherapy in manic episodes from moderate to severe severity. Data on the use of quetiapine in combination with semenotrial valproate or lithium preparations for moderate to severe manic episodes are limited, but this combination therapy was generally well tolerated. Besides, quetiapine at a dose of 300 mg and 600 mg is effective in patients with type I and II bipolar disorder from moderate to severe severity. In this case, the effectiveness of quetiapine when taken at a dose of 300 mg and 600 mg per day is comparable.

Quetiapine is effective in patients with schizophrenia and mania when taking the drug 2 times a day, despite the fact that the half-life of quetiapine is about 7 hours. The effect of quetiapine on 5HT₂- and D₂-receptors lasts up to 12 hours after taking the drug.

When quetiapine was administered with a dose titration in schizophrenia, the frequency of EPS and the concomitant use of m-holinoblockers was comparable to that of placebo. When quetiapine was administered in fixed doses from 75 to 750 mg / day in patients with schizophrenia, the incidence of EPS and the need for concomitant use of m-holinoblokatorov did not increase.

With the use of quetiapine in doses up to 800 mg / day for the treatment of manic episodes from moderate to severe severity, either as monotherapy or in combination with lithium preparations or semifloric valproate, the frequency of EPS and the concomitant use of m-holinoblockers was comparable to that of admission placebo.

In a clinical trial in patients with depressive episodes in the structure of type I or II bipolar disorder, the use of quetiapine at a dose of 300 mg / day with a higher efficacy than in the placebo group reduced the overall score on the Montgomery-Asberg depression scale (MADRS). In four additional clinical trials of quetiapine, duration 8 weeks in patients with moderate and severe depressive episodes in the structure of type I or II bipolar disorder quetiapine in doses of 300 mg and 600 mg showed a higher than placebo, the effectiveness of the relevant indicators: the average improvement in scores of the scale MADRS and improvement in the overall score MADRS (not less than 50%) in comparison with the initial value. The effectiveness of quetiapine when taken at a dose of 300 mg and 600 mg per day is comparable.

Data on the prolonged use of quetiapine for the prevention of subsequent manic and depressive episodes are absent.

Clinical safety

Quetiapine does not cause a prolonged increase in the concentration of prolactin in the blood plasma. In numerous studies with a fixed dose, there was no difference in the level of prolactin when using quetiapine or placebo.

In placebo-controlled trials in elderly patients with dementia with quetiapine, the incidence of cerebrovascular complications did not exceed those in the placebo group.

Pharmacokinetics:

When administered orally quetiapine well absorbed from the gastrointestinal tract and actively metabolized in the liver.

The intake of food does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine binds to plasma proteins.

The equilibrium molar concentration of the active metabolite N-dealkylkvetiapine is 35% of that of quetiapine. The half-life of quetiapine and Nis about 7 and 12 hours, respectively. The pharmacokinetics of quetiapine and N-desalkilkvetiapine is linear, there are no differences in pharmacokinetic parameters in men and women.

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

The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min / 1.73 m²). In patients with hepatic insufficiency (compensated alcoholic cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%. Because the quetiapine is intensively metabolized in the liver, in patients with hepatic insufficiency it is possible to increase the plasma concentration of quetiapine, which requires a dose adjustment.

On average less than 5% molar dose fraction of free quetiapine and N-descalklykvetiapine plasma are excreted by the kidneys. Approximately 73% of quetiapine is excreted by the kidneys and 21% by the intestine. Less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or through the intestine.

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 a concentration of 5-50 times the concentration observed at the usual effective dosage of 300-800 mg / day.

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

Indications:

For treatment:

- schizophrenia;

- manic episodes in the structure of bipolar disorder;

- depressive episodes from medium to severe severity in the structure of bipolar disorder.

The drug is not indicated for the prevention of manic and depressive episodes.

Contraindications:

- Hypersensitivity to any of the components of the drug, including lactase deficiency, glucose-galactose malabsorption and intolerance to galactose;

- combined use with cytochrome P450 inhibitors, such as antifungal agents of the azole group, erythromycin, clarithromycin and nefazodone, as well as HIV protease inhibitors (see section "Interaction with other drugs");

- age to 18 years.

Carefully:

- In patients with cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension;

- elderly age;

- liver failure;

- convulsive seizures in the anamnesis;

- risk of stroke;

- risk of aspiration pneumonia.

Pregnancy and lactation:

The safety and efficacy of quetiapine in pregnant women have not been established. Therefore, during pregnancy quetiapine It can only be used if the expected benefit for a woman justifies the potential risk to the fetus.

When using antipsychotics, including quetiapine, in the third trimester of pregnancy, neonates have a risk of developing adverse reactions of varying severity and duration, including EPS and / or withdrawal syndrome. There was reported on excitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome or feeding disorders. In this regard, you should carefully monitor the condition of newborns.

Quetiapine excretion with breast milk has been reported, but excretion has not been established. Women should be advised to avoid breastfeeding while taking quetiapine.

In experimental studies on animals there was no mutagenic and clastogenic action of quetiapine. For quetiapine in doses less than 1/4 of the maximum recommended dose for human (800 mg), embryo and fetotoxic effects are not established. There are data on the embryotoxicity of quetiapine, which was manifested when applied in rats and rabbits at doses equivalent to one or two of the maximum recommended doses of quetiapine for humans,in the form of a delay in the skeletal ossification of young rats and rabbits, and in the form of an increase in the incidence of minor abnormalities of the soft tissues of the cubs' limbs. Also at doses equivalent to two maximum recommended doses for humans, the toxic effect of quetiapine on the body of pregnant animals (female rats and rabbits) was noted, which manifested itself as a reduction in the body weight of females and / or an increase in mortality among them. When quetiapine was administered to pregnant female rats at doses equivalent to three maximum recommended doses for humans, there was an increase in mortality in offspring in the pre- and postnatal periods.

The negative effect of quetiapine on fertility in rats (decreased male fertility, pseudopregnancy, an increase in the period between two estrus, an increase in the precoital interval, and a decrease in the frequency of pregnancy) were revealed. However, you can not directly transfer the received data to a person, because there are specific differences in the hormonal control of reproduction.

Dosing and Administration:

There are various quetiapine treatment regimens for each indication.The physician should provide the patient with clear instructions for dosing the drug and make sure that patients receive sufficient information about taking quetiapine, which is appropriate for their condition,.

Quetiapine can be used regardless of food intake.

Adults

Treatment of schizophrenia

Quetiapine is administered twice a day. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. Starting from the 4th day the dose should be selected up to an effective dose, usually in the range of 300 to 450 mg / day. Depending on the clinical effect and individual patient tolerance, the dose may vary from 150 to 750 mg / day. The maximum recommended daily dose is 750 mg.

Treatment of manic episodes in the structure of bipolar disorder

Quetiapine is used as a monotherapy or in combination with drugs that have a normotimic effect.

Quetiapine is administered twice a day. The daily dose for the first 4 days of therapy is: 1st day - 100 mg, 2nd day - 200 mg, 3rd day - 300 mg, 4th day - 400 mg. In the future, 6The day of therapy, the daily dose of the drug can be increased to 800 mg. The increase in the daily dose should not exceed 200 mg per day.

Depending on the clinical effect and individual tolerability, the dose may vary from 200 to 800 mg / day. Usually the effective dose is from 400 to 800 mg / day. The maximum recommended daily dose is 800 mg.

Treatment of depressive episodes in the structure of bipolar disorder

Quetiapine is prescribed once a day at night. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. The recommended dose is 300 mg / day. The maximum recommended daily dose of the drug Quetiapine is 600 mg,

The antidepressant effect of quetiapine was confirmed when used at a dose of 300 and 600 mg / day. With short-term therapy, the effectiveness of quetiapine in doses of 300 and 600 mg / day was comparable (see the section "Pharmacodynamics").

Elderly

In elderly patients, the initial dose of quetiapine is 25 mg / day. The dose should be increased daily by 25-50 mg until an effective dose is obtained, which is likely to be less than in young patients.

In elderly patients quetiapine (as well as other neuroleptics) should be used with caution, especially at the beginning of therapy. Selection of the effective dose of the drug Quetiapine these 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 addition, patients of this group are more likely to have liver, kidney, nervous and cardiovascular disease, and concomitant medications are also more often prescribed.

Patients with renal insufficiency

A dose adjustment is not required.

Patients with hepatic insufficiency

Quetiapine is extensively metabolized in the liver. Therefore, caution should be exercised when using it in patients with hepatic impairment, especially at the onset of therapy. It is recommended to begin therapy with quetiapine at a dose of 25 mg / day and increase the dose daily by 25-50 mg until an effective dose is reached.

Side effects:

The most common side effects of quetiapine (> 10%) are drowsiness, dizziness, dry mouth, withdrawal syndrome, increased triglyceride concentration, increased total cholesterol concentration (mainly low-density lipoprotein cholesterol-LDL cholesterol), a decrease in high-density lipoprotein cholesterol (HDL), weight gain, decreased hemoglobin concentration, and extrapyramidal symptoms.

Classification of the incidence of adverse events (WHO): very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000); very rarely (<1/10 000), including individual messages; the frequency is unknown: according to the available data, it is not possible to establish the frequency of occurrence.

From the central nervous system:

very often - dizziness^1,4,17, drowsiness^1,2,17, headache¹⁰, extrapyramidal symptoms^1,13;

often - dysarthria, unusual and nightmarish dreams, suicidal thoughts and behavior¹, increased appetite;

infrequently - cramps, restless leg syndrome, tardive dyskinesia¹, faint^1,4,17,26; rarely - somnambulism and similar phenomena.

From the gastrointestinal tract:

very often - dry mouth;

often - constipation¹, dyspepsia, vomiting^10,21;

infrequently - dysphagia^1,8;

rarely - intestinal obstruction / ileus¹, pancreatitis¹;

On the part of the hematopoiesis system:

often - leukopenia^1,25 , decrease in the number of neutrophils^1,22 , an increase in the number of eosinophils²⁴;

infrequently - thrombocytopenia¹⁴, a decrease in the number of platelets¹⁴, anemia;

rarely - agranulocytosis^1,27;

frequency is unknown - neutropenia¹.

From the cardiovascular system:

often - tachycardia^1,4;

orthostatic hypotension^1,4,17, a feeling of heartbeat¹⁹;

infrequently bradycardia²⁶, lengthening the interval QT^1,13,20;

rarely - venous thromboembolism¹.

From the respiratory system:

often shortness of breath¹⁹; infrequently - rhinitis.

From the side of the kidneys and urinary tract:

infrequently urinary retention.

From the liver and bile ducts:

rarely - jaundice⁶, hepatitis⁶.

From the immune system:

infrequently - hypersensitivity reactions;

very rarely - anaphylactic reactions⁶.

On the part of the reproductive system:

infrequently - sexual dysfunction;

rarely - priapism, galactorrhea, disorders of the menstrual cycle.

From the skin and subcutaneous tissues:

very rarely - angioedema⁶, Stevens-Johnson syndrome⁶.

From the musculoskeletal and connective tissue:

very rarely - rhabdomyolysis.

From the side of the organ of vision:

often - blurred vision.

Metabolic disorders:

infrequently - diabetes mellitus^1,3,6.

Changes in laboratory and instrumental indicators:

very often - an increase in the concentration of triglycerides^1,11, an increase in the concentration of total cholesterol (mainly low density lipoprotein cholesterol - LDL)^1,12, a decrease in the concentration of high-density lipoprotein cholesterol (HDL)^1,18, weight gain⁹, decrease in hemoglobin concentration²³;

often - increased activity of alanine aminotransferase (ALT)³, gamma-glutamyl transpeptidase (GGT)³, hyperglycemia^1,7, increased concentration of prolactin in the blood plasma¹⁶, a decrease in the concentration of total and free T₄²⁰, decrease in the concentration of the total T3²⁰, an increase in thyroid-stimulating hormone (TSH)²⁰;

infrequently - increased activity of aspartate aminotransferase (ACT)³, a decrease in the concentration of free T₃²⁰, hyponatraemia²⁹;

rarely - increased activity of creatine phosphokinase¹⁵;

very rarely - the syndrome of inadequate secretion of antidiuretic hormone.

General disorders:

very often - the syndrome of "cancellation"^1,10;

often - slightly expressed asthenia, irritability, peripheral edema, fever;

rarely - malignant neuroleptic syndrome¹, hypothermia;

frequency unknown - withdrawal syndrome in newborns²⁸ .

1. See section "Special instructions"

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

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

4. Like other antipsychotics with α₁adrenoblocking action, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia, in some cases - fainting, especially at the beginning of therapy (see section "Special instructions"),

5. Very rare cases of decompensation of diabetes mellitus have been noted.

6. The frequency of this side effect was estimated based on the results of post-marketing research.

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

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

9. Increase in the initial body weight by at least 7%. Basically, it occurs at the beginning of therapy in adults.

10. In the study of the syndrome of "withdrawal" in short-term placebo-controlled trials of quetiapine in the monotherapy regime,the following symptoms are noted: insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability. The frequency of the "withdrawal" syndrome was significantly reduced 1 week after quetiapine was discontinued.

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

12. Increase in total cholesterol concentration ≥ 240 mg / dl (≥ 6.2064 mmol / L) in patients older than 18 years of age or ≥ 200 mg / dl (≥ 5.172 mmol / L) in patients <18 years of age, at least once.

13. See further in the text of the Instruction.

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

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

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

17. Can lead to a fall.

18. Reducing the concentration of HDL cholesterol <40 mg / dl (<1.03 mmol / l) in men and

< 50 mg / dl (<1.29 mmol / l) in women.

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

20. Based on potentially clinically significant deviations from the normal baseline observed in all clinical trials. Changes in the concentration of the total T₄, free T₄, the total T₃, free T₃ to values <80% of the lower limit of the norm (pmol / L) when measured at any time. Change in the concentration of TTG> 5 mI / d when measured at any time.

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

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

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

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

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

26. It can develop at the time or after the start of therapy and is accompanied by hypotension and / or fainting. The frequency is based on reports of bradycardia and related adverse events in all clinical studies of quetiapine.

27. Based on the frequency estimate in patients who participated in all clinical studies of quetiapine who had severe neutropenia (<0.5 x 10⁹/ l) in combination with infections.

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

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

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

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

ESR frequency in short-term clinical studies in adult patients with schizophrenia and mania in bipolar disorder structure was comparable in the placebo group and quetiapine (patients with schizophrenia: 7.8% quetiapine group and 8.0% in the placebo group; mania of bipolar disorder in the structure : 11.2% in the quetiapine group and 11.4% in the placebo group).

The incidence of EPS in short-term clinical trials in adult patients with depression in the structure of bipolar disorder in the quetiapine group was 8.9%, in the placebo group 3.8%. In this case, the frequency of individual symptoms of EPS (such as akathisia,extrapyramidal disorders, tremor, dyskinesia, dystonia, anxiety, involuntary muscle contractions, psychomotor agitation, and muscle rigidity) was generally low and did not exceed 4% in each of the therapeutic groups. In long-term clinical studies of quetiapine in schizophrenia and bipolar disorder in adult patients, the incidence of EPS was comparable in quetiapine and placebo groups.

Against the background of quetiapine therapy, a dose-dependent decrease in the concentration of thyroid hormones can be noted. The frequency of potentially clinically significant changes in the concentration of thyroid hormones in short-term clinical trials for general T₄ was 3.4% in the quetiapine group and 0.6% in the placebo group; for free T₄- 0.7% in the quetiapine group versus 0.1% in the placebo group; for the general T₃ - 0.54% in the quetiapine group against 0,0% in the placebo group; for free T₃ - 0,2 % in the quetiapine group versus 0.0% in the placebo group. The change in TSH concentration was noted with a frequency of 3.2% in the quetiapine group and 2.7% in the placebo group. In short-term clinical trials of monotherapy, the frequency of potentially clinically significant changes in T₃ and TTG was 0.0% in the quetiapine group and placebo; for T₄ and TTG was 0.1% in the quetiapine group versus 0.0% in the placebo group. These changes, as a rule, are not associated with clinically pronounced hypothyroidism. Maximum reduction in total and free T₄ registered on 6week treatment with quetiapine, without further reducing the concentration of hormones during long-term treatment. In practically all cases, the concentration of the total and free T₄ returned to baseline after quetiapine therapy was discontinued, regardless of the duration of treatment. The concentration of thyroxin-binding globulin (TSH) when measured at 8 patients remained unchanged.

Overdose:

A lethal outcome was reported when 13.6 g quetiapine was taken from a patient who participated in a clinical trial, as well as a fatal outcome after taking 6 g quetiapine in a post-marketing study. At the same time, a case of taking quetiapine in a dose exceeding 30 g is described, without a lethal outcome.

There are reports of extremely rare cases of quetiapine overdose that led to an increase QTc interval, 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 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 no specific antidotes to quetiapine. In cases of severe intoxication, one should remember about the possibility of an overdose with several medications. It is recommended to carry out activities aimed at maintaining the function of respiration and cardiovascular system, ensuring adequate oxygenation and ventilation. Reports have been published on the resolution of severe adverse effects from the central nervous system, including coma and delirium, after intravenous injection of physostigmine (1-2 mg) under constant ECG monitoring.

In case of occurrence of refractory hypotension in case of quetiapine overdose treatment should be carried out by intravenous fluid and / or sympathomimetic drugs (should not be prescribed epinephrine and dopamine, since stimulation of β-adrenergic receptors can cause an increase in hypotension while blocking α-adrenergic receptors with quetiapine).

Gastric lavage (after intubation, if the patient is unconscious), the appointment 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. It is also not recommended to take quetiapine together with grapefruit juice.

In a pharmacokinetic study with multiple administration of quetiapine prior to or concomitant with carbamazepine, a significant increase in clearance of quetiapine was shown 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 the blood plasma and may reduce the effectiveness of quetiapine therapy. Co-administration of quetiapine with phenytoin, another inducer of the microsomal system of the liver, 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 CYP2D6) or fluoxetine (inhibitor CYP3A4 and CYP2D6).

The pharmacokinetics of quetiapine does not change significantly when administered simultaneously with antipsychotic drugs risperidone or haloperidol. However, simultaneous administration of quetiapine and thioridazine led to an increase in the clearance of quetiapine by approximately 70%.

The pharmacokinetics of quetiapine does not change significantly with the simultaneous use of cimetidine.

With a single admission of 2 mg of lorazepam against quetiapine at a dose of 250 mg twice daily, the clearance of lorazepam decreases 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.

In groups of patients concurrently taking quetiapine and valproic acid medications, including those in the prolonged dosage form, as well as a combination of valproate with quetiapine, higher levels of leukopenia and neutropenia were observed compared to the monotherapy groups.

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 extend the interval QTc, including antiarrhythmic drugs of class 1A (for example, quinidine, procainamide), or class 3 (for example, amiodarone, sotalol), antibiotics (for example, gatifloxacin, moxifloxacin), or other drugs that extend the interval QTc (e.g., pentamidine, methadone, etc.). When quetiapine was used, cases of lengthening of the interval QTc in patients with concomitant diseases, in patients taking medications that cause electrolyte imbalance or an increase in the interval QTc, as well as with an overdose of quetiapine.

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 18 years)

A drug quetiapine is not indicated for use in children and adolescents under 18 due to insufficient data on use in this age group. According to the results of clinical studies, some side effects (increased appetite, increased concentration of prolactin in plasma 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 frequency of EPS was higher with quetiapine compared with placebo.

Suicide / suicidal thoughts or clinical worsening

Depression in bipolar disorder is associated with an increased risk of suicidal thoughts, self harm and suicide (events related to suicide). This risk remains until the onset of severe remission.In view of the fact that before the improvement of the patient's condition from the beginning of treatment, several weeks or more may pass, patients should be under close medical supervision before the onset of improvement. According to the generally accepted clinical experience, the risk of suicide may increase in the early stages of the onset of remission.

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.According to clinical studies in patients, suicide occurred in 3.0% of cases of quetiapine versus 0% placebo in persons under 25 years of age.

Conducted FDA (US Food and Drug Administration), a meta-analysis of placebo-controlled studies 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 antidepressant medications children, adolescents and adult patients under the age of 25 years. This meta-analysis did not include studies where it was used quetiapine (see the section "Pharmacodynamics").

Drowsiness

During treatment with quetiapine, drowsiness and related symptoms may occur, for example sedation (see "Side effect"), In clinical trials involving patients with depression in the structure of bipolar disorder, drowsiness usually developed during the first three days of therapy . The severity of this side effect was mostly mild or moderate. With the development of severe drowsiness, patients with depression in the structure of bipolar disorder may need more frequent visits to the doctor during 2 weeks from the onset of drowsiness or to a decrease in the severity of symptoms. In some cases quetiapine therapy may be discontinued.

Dizziness

Treatment with quetiapine can cause orthostatic hypotension and, as a result, dizziness, which occurs, as a rule, in the initial period of dose selection. Dizziness may increase the risk of accidental injuries (falls), especially in elderly patients. Therefore, patients should be cautious at the beginning of the drug.

Patients with cardiovascular diseases

Caution should be exercised when assigning quetiapine to patients with cardiovascular and cerebrovascular diseases and other conditions, predisposing to hypotension. On the background of quetiapine therapy, orthostatic hypotension may occur, especially during dose selection at the beginning of therapy. When orthostatic hypotension occurs, a dose reduction or a slower increase in dose may be required.

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.

Convulsive seizures

There were no differences in the incidence of seizures in patients who took quetiapine or placebo. However, as with other antipsychotic drugs, caution should be exercised in the treatment of patients with a history of seizures (see "Side effects"),

Extrapyramidal symptoms

An increase in the incidence of EPS in adult patients with depression in the structure of bipolar disorder with quetiapine for depressive episodes compared with placebo has been noted (see "Side effect").

Late dyskinesia

There is a possibility of an increased risk of developing tardive dyskinesia with an increase in the duration of treatment and the total cumulative dose of the drug. Nevertheless, the syndrome can develop after relatively short courses at low doses. Despite the fact that the prevalence of tardive dyskinesia is higher among elderly patients, especially older women, it is impossible to assess the likelihood of its development in different patients.Treatment with antipsychotic drugs can suppress (partially suppress) the symptoms and thereby hide the underlying process.

In case of development of symptoms of tardive dyskinesia, it is recommended to reduce the dose of the drug or gradually cancel it (see the section "Side effect").

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, it is necessary to cancel quetiapine and conduct appropriate treatment.

Severe neutropenia and agranulocytosis

In the short-term placebo-controlled clinical trials of monotherapy with quetiapine, cases of severe neutropenia 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 in postmarketing use (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 number of leukocytes and cases of drug-induced neutropenia in a history.

The development of agranulocytosis was also noted in patients without risk factors. It is necessary to consider the possibility of developing neutropenia in patients with infection, especially in the absence of obvious predisposing factors, or in patients with unexplained fever; these cases should be conducted in accordance with clinical recommendations.

In patients with a neutrophil count <1.0 x 10⁹/ l, quetiapine should be discontinued. The patient should be observed to identify possible symptoms of infection and control the level neutrophils (before exceeding the level of 1.5 x 10⁹/ l).

Interaction with other drugs

Also seesection "Interaction with other medicines".

The use of quetiapine in combination with strong 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 quetiapine therapy.

The administration of quetiapine to patients receiving inductors 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 enzymes (for example, preparations of valproic acid).

Hyperglycaemia

On the background of quetiapine, hyperglycemia may develop: an increase in fasting blood glucose ≥126 mg / dl (≥7.0 mmol / l) or postprandial blood glucose ≥200 mg / dL (≥11.1 mmol / l) a single definition or exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, in patients with diabetes mellitus in history.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).

Lipid content

Against the background of taking quetiapine, an increase in the concentration of triglycerides and cholesterol, as well as a decrease in the concentration of HDL is possible (see the section "Side effect").

Metabolic disorders

An increase in body weight, an increase in the concentration of glucose and lipids in the blood in some patients can lead to a deterioration in the metabolic profile, which requires appropriate monitoring. Perhaps an asymptomatic increase (≥3 times the upper limit of the norm when measured at any time) of ALT, ACT and GGT activity in the blood plasma is usually reversible against the background of continued use of quetiapine.

Body mass

As a result of the 6of a weekly placebo-controlled clinical trial of quetiapine showed a more than 7% increase in the body weight of patients in the treatment of schizophrenia during the use of quetiapine (23% of the quetiapine group compared to 6% of the placebo group), with monotherapy of mania (21% of quetiapine group compared with 7% placebo group), and as part of combination therapy, 13% of the patients in the group who received quetiapine, compared with 4% placebo. In the treatment of depression in bipolar disorder, there was an increase in body weight 8% of patients who received quetiapine against 2% of the group receiving the placebo. In this regard, a basic and regular monitoring of body weight of patients should be carried out.

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 quetiapine (see section "Overdose"). Caution should be exercised when assigning quetiapine, as well as other antipsychotics, to patients with cardiovascular disease and the previously noted lengthening of the interval QT. Also, care should be taken when administering quetiapine concurrently with drugs that extend the interval QTc, other neuroleptics, especially in the elderly, in patients with the syndrome of congenital lengthening of the interval QT, 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, it is recommended to cancel the drug gradually for at least one or two weeks.

Elderly patients with dementia

Quetiapine 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 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 death rate in the group of patients receiving drugs of this group, compared with the placebo group.

In addition, two 10-week placebo-controlled studies of quetiapine in a similar group of patientsn= 710; average age: 83 years; age range: 56-99 years) showed that the mortality rate in the group of patients taking quetiapine, was 5.5% and 3.2% in the placebo group. The causes of deaths observed in these patients were consistent with those expected for this population. There was no causal relationship between the treatment of quetiapine and the risk of increased mortality in elderly patients with dementia.

Disorders from the side of the liver

In the case of jaundice, taking the drug 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.

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 Fig.Side effects), including fatal cases in patients at high risk of intestinal obstruction, including those receiving multiple concomitant medications that reduce intestinal motility, even in the absence of complaints of constipation.

Pancreatitis

During clinical trials, post-marketing research and post-marketing use, cases of pancreatitis development were noted, but a causal relationship with the drug intake was not established. Post-marketing reports indicate that many patients there were risk factors for pancreatitis, such as increased triglyceride concentrations, cholelithiasis and alcohol use.

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

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

Form release / dosage:

Film-coated tablets, 25 mg, 100 mg, 200 mg and 300 mg.

Packaging:

10, 15, 20 or 30 tablets in a planar cell packaging made of a polyvinylchloride film and aluminum foil.

30, 60 or 90 tablets in a can of high-density polyethylene.

1, 2 or 3 contourcell packs of 30 tablets, 3 contour packs of 20 tablets, 2, 4 or 6 contiguous cell packs of 15 tablets, 3 or 6 contiguous cell packs of 10 tablets or one bank together with instructions for medical use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002688

Date of registration:31.10.2014 / 01.06.2017

Expiration Date:31.10.2019

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp27.12.2017

Illustrated instructions

Instructions

Quetiapine (Quetiapine)