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

Excipients: cellulose microcrystalline 21.0 mg / 42.0 mg / 84.0 mg; lactose monohydrate 40.92 mg / 24.27 mg / 48.54 mg, carboxymethyl starch sodium (sodium starch glycolate) 7.0 mg / 14.0 mg / 28.0 mg; giprolose (hydroxypropylcellulose) 1.3 mg / 2.6 mg / 5.2 mg, magnesium stearate 1.0 mg / 2.0 mg / 4.0 mg;

excipients for the shell: giprolose (hydroxypropylcellulose) 2.1 mg / 4.2 mg / 8.4 mg; macrogol 6000 (polyethylene glycol 6000) 0.6 mg / 1.2 mg / 2.4 mg, titanium dioxide 0.29 mg / 0.36 mg / 1.2 mg; dye azorubin (carmoazine) 0.01 mg / 0 mg / 0 mg, iron oxide yellow 0 mg / 0.24 mg / 0 mg.

Description:

Dosage of 25 mg: tablets, covered with a film shell of pink color, biconvex, oblong with rounded ends, with a risk.

Dosage of 100 mg: The tablets covered with a film cover of yellow color, round, biconcave form.

Dosage 200 mg: tablets, coated with a white film shell, biconvex, oblong with rounded ends, with a risk.

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 (norquetiapine) interact with a wide range of neutron-transmitting receptors in the brain. Quetiapine and N-desalkylketiapine show a high affinity for serotonin 5HT receptors₂-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, causes clinical antipsychotic properties of quetiapine and a low incidence of extrapyramidal disorders. Quetiapine has no affinity for the carrier of norepinephrine and has a low affinity for 5HT_]A-serotonin receptors, manifested N-dealkylkvetiapine, can cause antidepressant effect of the drug. Quetiapine and N-dealkalketiapine have a high affinity for histamine and α₁adrenoreceptors and moderate affinity for α₂adrenoreceptors. Besides quetiapine It does not possess or has a low affinity for muscarinic receptors, while N-dealkylketiapine exhibits moderate or high affinity for several subtypes of muscarinic receptors.

In standard tests 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 D₂-receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10-dopaminergic neurons in comparison with A9-nigrostriate neurons involved in motor function.

Efficiency

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 prolonged use of quetiapine for the prevention of subsequent manic and depressive episodes are absent.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 receptors of the type 5NT2- 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. In appointing quetiapine 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 or valproate semiotria, the incidence of EPS and concomitant use of m-holinoblockers was comparable to that of admission placebo.

Pharmacokinetics:

Ingestion 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 N- Dealkalkvetiapine is 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 /1,73m²), but individual clearance rates are within the values found in healthy volunteers. In patients with hepatic insufficiency (compensated alcoholic cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%. Because the quetiapine is intensively metabolized in the liver, in patients with hepatic insufficiency it is possible to increase the plasma concentration of quetiapine, which requires a dose adjustment.

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

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 with respect to the isoenzymes of the cytochrome P system450 1A2, 2C9, 2C19, 2D6 and 3A4, but only at concentrations 5-50 times higher than the concentrations observed at the usual effective dosage of 300-800 mg / day.

Based on the results in vitro, one should not expect that simultaneous use of quetiapine with other drugs will result in a clinically pronounced inhibition of the metabolism of other medicaments mediated by cytochrome P450.

Indications:

For the treatment of schizophrenia.

For the treatment of manic episodes in the structure of bipolar disorder.

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

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

Contraindications:

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

Simultaneous use 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").

Despite the fact that the effectiveness and safety of quetiapine in children and adolescents aged 10-17 years have been studied in clinical studies, the use of the drug in patients under the age of 18 years is not indicated.

Carefully:

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

Pregnancy and lactation:

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

When using antipsychotic drugs, including quetiapine, in the third trimester of pregnancy, neonates have the risk of developing adverse reactions of varying severity and duration. Including EPS and / or "cancellation" 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. However, the degree of excretion is not established. Women should be advised to avoid breastfeeding while taking quetiapine.

Dosing and Administration:

The drug can be used regardless of food intake.

Adults

Treatment of schizophrenia

The drug is prescribed 2 times a day. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3rd day - 200 mg, 4th day - 300 mg. Starting from the 4th day, the dose should be selected 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

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

The drug is prescribed 2 times a day. The daily dose for the first 4 days of therapy is: 1st day - 100 mg, 2nd day - 200 mg, 3rd day - 300 mg, 4th day - 400 mg. In the future, 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

The drug 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 is 600 mg.

The antidepressant effect of quetiapine was confirmed when applied 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 patients

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

Patients with renal insufficiency

A dose adjustment is not required.

Patients with hepatic insufficiency

Quetiapine is extensively metabolized in the liver. Therefore, care should be taken when using the drug in patients with hepatic insufficiency, especially at the beginning of therapy.It is recommended to start therapy with 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 frequent adverse reactions with quetiapine (≥10%) are drowsiness, dizziness, dry mouth, withdrawal syndrome, increased triglyceride concentration, increased total cholesterol concentration (mainly low-density lipoprotein cholesterol (LDL), lowering of lipoprotein cholesterol high density (HDL), weight gain, decreased hemoglobin concentration, and extrapyramidal symptoms.

The frequency of unwanted reactions is as follows: 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). Undesirable reactions, the frequency of development of which can not be estimated from available data, have the designation "frequency is unknown".

From the central nervous system: very often - dizziness^1,4,17, drowsiness^2,17, headache, extrapyramidal symptoms^1,13 often - dysarthria, unusual and nightmarish dreams, increased appetite; infrequently - convulsions¹, restless legs syndrome, tardive dyskinesia¹, faint^1,4,17; rarely - somnambulists and similar phenomena.

From the gastrointestinal tract: very often - dry mouth; often - constipation, indigestion, vomiting²¹ ; infrequently - dysphagia^1,8 ; rarely - an intestinal obstruction / ileus.

On the part of the hematopoiesis system: often - leukopenia^1,25; frequency is unknown - neutropenia¹.

From the side of the cardiovascular system: often - tachycardia^1,4, palpitations¹⁹, orthostatic hypotension^1,4,17; infrequently bradycardia²⁶.

From the side of the organ of vision: often - blurred vision.

From the respiratory system: often shortness of breath¹⁹; infrequently - rhinitis.

From the immune system: infrequently - hypersensitivity reactions; very rarely - anaphylactic reactions⁶.

From the side of the kidneys and urinary tract: infrequently urinary retention.

From the liver and biliary tract: rarely - jaundice⁶; very rarely - hepatitis⁶.

From the side of the reproductive system: rarely - priapism, galactorrhea.

Metabolic disorders: very rarely - diabetes mellitus^1,5,6.

From the skin and subcutaneous tissues: very rarely - angioedema⁶, Stevens-Johnson syndrome⁶.

Changes in laboratory and instrumental indicators: very often - an increase in the concentration of triglycerides^1,11, total cholesterol (mainly LDL cholesterol)^1,12 , a decrease in the concentration of HDL cholesterol^1,18, weight gain⁹, decrease in hemoglobin concentration²³; often - increased ALT activity³, an increase in GGT activity³, decrease in the number of neutrophils^1,22, an increase in the number of eosinophils²⁴, hyperglycemia^1,7, increased concentration of prolactin in the blood serum¹⁶, a decrease in the concentration of total and free T4²⁰, a decrease in the concentration of the total T₃²⁰, increased concentration of TSH²⁰; infrequently - increased activity ACT³, thrombocytopenia¹⁴, lengthening the interval QT^1,13, a decrease in the concentration of free T₃²⁰; rarely - increased activity of creatine phosphokinase¹⁵, agranulocytosis²⁷.

General disordersa: 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 backdrop of continued use of quetiapine.

3. Perhaps an asymptomatic increase (≥ 3 times the upper limit of the norm when measured at any time) of 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 antipsychotics with α₁-adrenoblocking 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 undesirable reaction was estimated based on the results of post-marketing surveillance.

7. An increase in fasting blood glucose ≥ 126 mg / dl (≥ 7.0 mmol / L) or post-prandial blood glucose ≥ 200 mg / dL (≥ 11,1 mmol / l), at least 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. When studying the withdrawal syndrome in short-term placebo-controlled clinical trials of quetiapine in monotherapy, the following symptoms were noted: insomnia, nausea, headache, diarrhea, vomiting,dizziness and irritability. The frequency of the "withdrawal" syndrome was significantly reduced 1 week after discontinuation of the drug.

11. Increase in triglyceride concentration ≥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.

13. See further in the text of the Instruction.

14. Decreased platelet count ≤100 x 10⁹/ l, at least for a single determination.

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

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

17. Can 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 the potentially clinically significant deviations from the normal baseline,noted 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> 5mMl / l when measured 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/ л cases of neutropenia (number of neutrophils <1.5х10⁹/ l) were observed in 1.9% of patients in the placebo group. Decrease in the number of neutrophils ≥0.5, but <1.0x10% was noted with a frequency of 0.2% in the quetiapine group and placebo. Decrease in the number of neutrophils <0.5x10⁹at least for a single determination is noted in 0,21 % patients in the quetiapine group 0% of the placebo group.

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

24. Based on potentially clinically significant deviations from the baseline normal level noted in all clinical trials. Increasing the number of eosinophils ≥1x10⁹/ l when measured at any time.

25. Based on potentially clinically relevant deviations from the baseline normal level noted in all clinical studies. Reducing the number of white blood cells ≥ 3x10⁹/ l when measured at any time.

26. It may develop at or soon after initiation of therapy and is accompanied by 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 taking part in all clinical studies of quetiapine who have had severe neutropenia (<0.5x10⁹/ l) at combination with infections.

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

Interval lengthening QT, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered undesirable reactions inherent in neuroleptics.

ESR frequency in short-term clinical studies in adult patients with schizophrenia and mania in bipolar disorder structure was comparable in the placebo group and quetiapine (patients with schizophrenia: 7.8% quetiapine group and 8.0% in the placebo group; mania of bipolar disorder in the structure : 11,2% in the quetiapine group and 11.4% in the placebo group).

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

Against the background of quetiapine therapy, there may be a small dose-dependent decrease in the concentration of thyroid hormones.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 versus 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 T₃and 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:

Symptoms

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 the post-marketing study of the drug. At the same time, the case of taking quetiapine in a dose exceeding 30 g is described, without a lethal outcome. There are reports of extremely rare cases of quetiapine overdose that led to an increase QTc interval, death or coma.

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

Symptoms noted in overdose were mainly due to increased known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and lowering blood pressure.

Treatment

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

If refractory hypotension occurs with an overdose of quetiapine treatment should be carried out by intravenous fluid and / or symptomatic drugs (should not be prescribed epinephrine and dopamine, since stimulation β-adrenoreceptors may cause an increase in hypotension in the background of blockade of a-adrenergic receptors with quetiapine).

Gastric lavage (after intubation, if the patient is unconscious) and 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 while using quetiapine with other drugs.drugs affecting the central nervous system, as well as with alcohol. Isozyme of cytochrome R₄₅₀ (CYP) 3A4 is the main isoenzyme responsible for the metabolism of quetiapine, carried out through the cytochrome system R₄₅₀. In healthy volunteers, simultaneous use of quetiapine (25 mg) with ketoconazole, an inhibitor of the CYP3A4 isoenzyme, resulted in an increase in the area under the concentration-time curve (AUC) of quetiapine 5-8 times.

Therefore, simultaneous use of quetiapine and inhibitors of the cytochrome isoenzyme 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 administration, a significant increase in quetiapine clearance and, accordingly, a decrease AUC, on average, by 13% compared with the use of quetiapine without carbamazepine. In some patients, a decrease AUC was even more pronounced. This interaction is accompanied by a decrease in the concentration of quetiapine in plasma and may reduce the effectiveness of quetiapine therapy. The simultaneous use of quetiapine with phenytoin, another inducer of microsomal liver enzymes,was accompanied by an even more pronounced (about 450%) increase in the clearance of quetiapine. The use of quetiapine in patients receiving inductors of the liver enzyme system is possible only if the expected benefit from therapy with the drug exceeds the risk associated with the cancellation of the inductor preparation of microsomal liver enzymes. The change in the dose of induction drugs 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). Pharmacokinetics quetiapine substantially not has changed at simultaneous use of an antidepressant imipramine (inhibitor CYP2D6) or fluoxetine (inhibitor CYP3A4 and CYP2D6).

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

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

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 enzyme immunoassay. To confirm the results of screening, a chromatographic study is recommended.

Special instructions:

Children and adolescents (aged 10 to 17 years)

The drug Cvetitex 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 a placebo-controlled studies in children of adolescents with schizophrenia and mania in bipolar disorder frequency structure of EPS was higher with quetiapine compared to 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.

According to clinical studies in patients with depression in bipolar disorder, the risk of suicidal events was 3.0% for quetiapine and 0% for placebo in patients aged 18-24 years; 1.8% for quetiapine and 1.8% for placebo for patients over 25 years of age.

Other psychiatric disorders for which therapy is prescribed quetiapineare also associated with an increased risk of suicidal events. In addition, such conditions can be comorbid with a depressive episode. Therefore, the precautions used in the therapy of patients with a depressive episode should be taken in the treatment of patients with other psychiatric disorders. With a sharp cessation of quetiapine therapy, the potential risk of suicidal events should be taken into account.

Patients with a history of suicidal events, as well as patients who clearly express suicidal thoughts before starting therapy, are at increased risk of suicidal intentions and suicidal attempts and should be carefully observed during treatment. Conducted FDA (The 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 adults with mental disorders, revealed an increased risk of suicidal behavior compared with placebo in children, adolescents and adult patients under the age of 25 years. This meta-analysis does not include studies where quetiapine (see the section "Pharmacodynamics").

According to the short-term, placebo-controlled studies in all indications and all age groups, frequency of events associated with suicide, was 0,8% for both quetiapine and placebo.

In these studies, patients with schizophrenia, the risk of events associated with suicide, was 1.4% for quetiapine and 1.6% for placebo in patients aged 18-24 years; 0.8% for quetiapine and 1.1% for patients over 25 years of age; 1.4% for quetiapine and 1.3% for placebo in patients under the age of 18 years.

In patients with mania in bipolar disorder, the risk of suicidal events was 0% for quetiapine and 0% for placebo in patients aged 18-24 years; 1.2% for quetiapine and 1.2% for placebo in patients older than 25 years; 1.0% for quetiapine and 0% for placebo in patients under the age of 18 years.

Drowsiness

During therapy, the drug may experience drowsiness and related symptoms, for example, sedation (see section "Side effect"). In clinical studies involving patients with depression in the structure of bipolar disorder, sleepiness tended to develop 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, discontinuation of therapy with the drug may be required.

Patients with cardiovascular diseases

Care should be taken when prescribing the drug to patients with cardiovascular and cerebrovascular diseases, and other conditions predisposing to hypotension.On the background of quetiapine therapy, orthostatic hypotension may occur, especially during titration of the dose at the beginning of therapy. If orthostatic hypotension occurs, a dose reduction or slower titration may be required.

Convulsive seizures

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

Extrapyramidal symptoms

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

Late dyskinesia

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

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 the drug and conduct appropriate treatment.

Severe neutropenia and agranulocytosis

In the short-term placebo-controlled clinical trials of quetiapine monotherapy, cases of severe neutropenia (number of neutrophils <0.5 x 10⁹/ l) without infection. Agranulocytosis (severe neutropenia associated with infections) was reported in patients who received quetiapine in clinical trials (rarely), as well as in 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 monitor the level of neutrophils (up to a level of 1.5 x 10⁹/ l).

Interaction with other drugs

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 blood plasma and can reduce the effectiveness of drug therapy.

Use of the drug in patients receiving inducers of microsomal liver enzymes, is possible only if the expected benefit from the treatment with quetiapine outweigh the risks associated with the abolition of the drug inducer 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).

Also see the section "Interaction with other drugs".

Hyperglycaemia

Against the background of taking quetiapine, it is possible to develop hyperglycemia or exacerbation of diabetes mellitus, in patients with diabetes mellitus in the anamnesis. Clinical observation is recommended for patients with diabetes mellitus and patients with risk factors for diabetes mellitus (see section "Side effect").

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.

QT interval extension

There was no correlation between the intake of quetiapine and the steady increase in the absolute value of the QT interval. However, the prolongation of the QT interval was noted with an overdose of the drug (see Fig.Overdose). Caution should be exercised when administering quetiapine, as well as other antipsychotics, to patients with cardiovascular disease and the previously noted QT interval elongation. Caution should also be exercised in appointing quetiapine concomitantly with QTc-prolonging drugs, other antipsychotics, especially in the elderly, in patients with congenital QT prolongation, chronic heart failure, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see "Interaction with other drugs ").

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

The drug is not indicated for the treatment of psychoses associated with dementia.

Some atypical antipsychotics in randomized, placebo-controlled trials are approximately 3-foldincreased the risk of developing cerebrovascular complications in patients with dementia. The mechanism of this increase in risk has not been studied. A similar risk of increasing the incidence of cerebrovascular complications can not be ruled out for other antipsychotic drugs or other groups of patients. The drug 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 patients (n = 710, mean age: 83 years, age range: 56-99 years) showed that the mortality rate in the group of patients taking quetiapine, was 5.5%, and 3.2% in the placebo group. The causes of deaths observed in these patients were consistent with those expected for this population. There was no causal relationship between quetiapine treatment and the risk of increased mortality in elderly patients with dementia.

Disorders from the side of the liver

If jaundice develops, stop taking the drug.

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 the "Side effect" section), including fatal cases in patients with a high risk of intestinal obstruction, including those receiving multiple concomitant medications that reduce intestinal motility, even in the absence of complaints for constipation.

Pancreatitis

During clinical trials and post-marketing use, cases of pancreatitis have been noted, but a causal relationship with the drug has not been established. Postmarketing reports indicate that many patients were at risk for developing pancreatitis,such as increasing the concentration of triglycerides (see subsection "Lipid content"), cholelithiasis and alcohol use.

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.

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.

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 treatment the drug does not recommend patients to drive vehicles, work with mechanisms and engage in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions,until the individual tolerability of therapy is established.

Form release / dosage:

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

Packaging:

For 10, 15, 20 or 30 tablets in a contoured cell packaging made of a polyvinylchloride film and aluminum foil printed lacquered.

By 1, 2, 3, 6, 10 or 12 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002696

Date of registration:06.11.2014

Expiration Date:06.11.2019

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Representation: & nbspOBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSCOBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSCRussia

Information update date: & nbsp28.12.2017

Illustrated instructions

Instructions

Cvetitex (Quetitex)