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Instruction for use: Kventiax

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Dosage form: semifinished-granulated packet (sachet) polyethylene

Active substance: Quetiapine*

ATX

N05AH04 Quetiapine

Pharmacological group:

Neuroleptics

The nosological classification (ICD-10)

F20 Schizophrenia: Schizophrenic conditions; Exacerbation of schizophrenia; Schizophrenia; Chronic schizophrenia; Dementia praecox; Bleuler's disease; Psychotic discordant; Dementia early; The febrile form of schizophrenia; Chronic schizophrenic disorder; Psychosis of the schizophrenic type; Acute form of schizophrenia; Acute schizophrenic disorder; Cerebral Organic Insufficiency in Schizophrenia; Acute attack of schizophrenia; Schizophrenic psychosis; Acute schizophrenia; Sluggish schizophrenia; Sluggish schizophrenia with apathoabulic disorders; Acute stage of schizophrenia with excitation

F31.1 Bipolar affective disorder, current episode of mania without psychotic symptoms: Mania in bipolar disorders

F31.2 Bipolar affective disorder, current episode of mania with psychotic symptoms: Manic episode of bipolar disorder; Mania in bipolar disorders

F32 Depressive episode: Adynamic subdepression; Astheno-adynamic subdepressive states; Asthenodepressive disorder; Astheno-depressive disorder; Asthenodepressive state; Astheno-depressive state; Major Depressive Disorder; Vyaloapatichesky depression with retardation; Double depression; Depressive pseudodement; Depressive illness; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive disorders; Depressive syndrome; Depressive syndrome larviated; Depressive syndrome with psychoses; Depressed masks; Depression; Depression Depletion; Depression with the phenomena of inhibition within the framework of cyclothymia; Depression is smiling; Involutional depression; Involutionary melancholy; Involutional depression; Manic-depressive disorder; Masked Depression; Melancholic Attack; Neurotic depression; Neurotic depression; Shallow Depression; Organic depression; Organic depressive syndrome; Simple depression; Simple melancholic syndrome; Psychogenic depression; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Reactive depression; Recurrent depression; Seasonal depressive syndrome; Severostatic depression; Senile Depression; Senile Depression; Symptomatic Depression; Somatogenic depression; Cyclotymic depression; Exogenous Depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

F33 Recurrent depressive disorder: Major depressive disorder; Secondary depression; Double depression; Depressive pseudodement; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive syndrome; Depressed masks; Depression; Depression is smiling; Involutional depression; Involutional depression; Masked Depression; Melancholic Attack; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Exogenous Depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

Composition

Tablets covered with a film membrane 1 tab.

core

active substance:

quetiapine fumarate (quetiapine hemifumarate) 115.13 mg

230.26 mg

345.39 mg

(equivalent to 100, 200 and 300 mg of quetiapine, respectively)

auxiliary substances: lactose monohydrate; calcium hydrogen phosphate dihydrate; ICC; povidone; sodium carboxymethyl starch (type A); magnesium stearate

membrane film: hypromellose; titanium dioxide (E171); macrogol 4000; colorant iron oxide yellow (E172)

Description of dosage form

Tablets of 100 mg: round, biconcave, film-coated pale yellow.

Type of tablet on a cross-section: a white rough surface with a cover of light yellow color.

Tablets of 200 mg: round, biconcave, covered with a film coat of white color.

Tablets of 300 mg: oval, biconcave, covered with a film coat of white color.

Type of tablets 200 mg and 300 mg in cross section: white rough surface with a white sheath.

Pharmachologic effect

Pharmacological action - antipsychotic, neuroleptic.

Pharmacodynamics

Mechanism of action. Quetiapine is an atypical antipsychotic. Quetiapine and its active metabolite N-desalkylkvetiapine (norquetiapine) interact with a wide range of neurotransmitter receptors in the brain. Quetiapine and N-desalkylketiapine show a high affinity for the 5-HT2-serotonin receptors and the D1-, D2-dopamine receptors of the brain.

With brief and long-lasting administration, quetiapine had a minimal ability to cause dystonia in capuchin monkeys sensitized with haloperidol or not receiving medication.

Clinical efficacy. 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 has generally been well tolerated. In addition, quetiapine in a dose of 300 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 and 600 mg / day is comparable. Quetiapine is effective in patients with schizophrenia and mania when taking the drug 2 times a day, despite the fact that T1 / 2 quetiapine is about 7 hours. The effect of quetiapine on 5-HT2- and D2-receptors continues 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.

Pharmacokinetics

Suction. Quetiapine is well absorbed from the digestive tract. Eating does not significantly affect bioavailability. Css molar active metabolite of N-desalkylkvetiapine is 35% of that of quetiapine.

The pharmacokinetics of quetiapine is linear.

Distribution. Approximately 83% of quetiapine binds to plasma proteins.

Metabolism. In vitro studies have shown that the CYP3A4 isoenzyme is the key isoenzyme of quetiapine metabolism, mediated by the cytochrome P450 system. N-dealkylkvetiapine is formed and excreted with the participation of the CYP3A4 isoenzyme.

Quetiapine and some of its metabolites (including N-dealkalkvetiapine) have a weak inhibitory activity against cytochrome P450 isoenzyme 1A2, 2C9, 2C19, 2D6 and 3A4 isoenzymes, but only at a concentration of 5-50 times the concentration observed at the commonly used effective dose 300-800 mg / day. Based on the results of in vitro studies, it should not be expected that simultaneous use of quetiapine with other drugs will lead to a clinically pronounced inhibition of the metabolism of other drugs mediated by the cytochrome P450 system.

Excretion. T1 / 2 quetiapine and N-desacilkvetiapine is about 7 and 12 hours, respectively. Approximately 73% of quetiapine is excreted by the kidneys and 21% by the intestine. Quetiapine is actively metabolized in the liver, less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or through the intestine.

Special patient groups

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

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

Impaired renal function. The average plasma clearance of quetiapine is reduced by approximately 25% in patients with severe renal insufficiency (Cl creatinine less than 30 ml / min / l, 73m2), but individual clearance rates are within the values found in healthy volunteers.

Violation of the function of the liver. In patients with hepatic insufficiency (compensated alcoholic cirrhosis), the mean plasma clearance of quetiapine is reduced by approximately 25%. Because quetiapine is extensively metabolized in the liver, in patients with hepatic insufficiency, an increase in the plasma concentration of quetiapine is possible, which requires dose adjustment.

Indications for Kventiax

treatment of schizophrenia;

treatment of manic episodes in the structure of bipolar disorder (not shown for the prevention of manic episodes);

treatment of depressive episodes from moderate to severe in the structure of bipolar disorder (not shown for the prevention of depressive episodes).

Contraindications

hypersensitivity to quetiapine or other components of the drug;

lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

age to 18 years (although the efficacy and safety of quetiapine in children and adolescents 10-17 years old have been studied in clinical trials, the use of Kventiax ® in patients under 18 years of age is not indicated).

With caution: cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension; elderly age; liver failure; convulsive seizures in the anamnesis; risk of stroke and aspiration pneumonia.

Application in pregnancy and lactation

Published data on the use during pregnancy (300-1000 pregnancy outcomes), including individual reports and observational data, did not show an increased risk of developing malformations during treatment. Nevertheless, based on the available data, it is impossible to draw a definite conclusion. Studies in animals have revealed the presence of reproductive toxicity. As a result, during pregnancy, quetiapine can only be used if the expected benefit to the mother justifies the potential risk to the fetus.

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

Quetiapine excretion with breast milk has been reported, but excretion has not been established. Due to the lack of reliable data, it is necessary to resolve the issue of stopping breastfeeding or abolishing Kventiax ®.

Side effects

Classification of the incidence of side effects recommended by WHO: very often - ≥1 / 10; often from ≥1 / 100 to <1/10; infrequently - from ≥1 / 1000 to <1/100; rarely - from ≥1 / 10000 to <1/1000; very rarely - from <1/10000; frequency is unknown - can not be estimated based on available data.

On the part of the blood and lymphatic system: very often - a decrease in Hb1; often - leukopenia2, 3, a decrease in the number of neutrophils, an increase in the number of eosinophils4; infrequently - thrombocytopenia, anemia, decrease in the number of thrombocytes5, neutropenia2; rarely - agranulocytosis6.

From the immune system: infrequently - hypersensitivity reactions (including allergic skin reactions); very rarely anaphylactic reactions.

On the part of the endocrine system: often - giperprolaktinemiya8, reducing the concentration of total and free thyroxine (T4) 9, reducing the concentration of total triiodothyrene (T3) 9, increasing the concentration of TSH9 in blood plasma; infrequent - a decrease in the concentration of free T39, hypothyroidism10; very rarely - the syndrome of inadequate secretion of ADH.

From the side of metabolism and nutrition: very often - an increase in the concentration of triglycerides (TG) in the blood serum, 11, 12, total Xc (mainly Xc LDL12, 13, decrease in HDL-C12, 14, weight gain12,15, increased blood glucose levels before hyperglycaemia12,16, infrequently - hyponatremia17, diabetes mellitus2,7, exacerbation of already existing diabetes mellitus, rarely - metabolic syndrome18.

From the side of the psyche: often - unusual and nightmarish dreams, suicidal thoughts and behavior19; rarely somnambulism and similar phenomena, such as sleep conversations and eating disorders associated with sleep.

From the nervous system: very often - dizziness20, 21, headache, drowsiness21, 22, EPS2, 10; often - dysarthria; infrequently - convulsions2, restless legs syndrome, late dyskinesia2, 7, fainting20, 21.

From the heart: often - tachycardia20, a feeling of heartbeat23; infrequent - prolongation of the interval QT2, 24, 25, bradycardia26.

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

From the side of the vessels: often - orthostatic hypotension 20, 21; rarely - VTE2.

On the part of the respiratory system, the organs of the thorax and the mediastinum: often - dyspnea; infrequently - rhinitis.

From the side of the digestive system: very often - dryness of the oral mucosa; often - indigestion, constipation, vomiting27; infrequently - dysphagia; rarely - pancreatitis2, intestinal obstruction / ileus.

From the liver and biliary tract: often - increased activity of transaminases in the blood plasma, ALT29, GGT29; infrequently - increased activity AST29; rarely, jaundice, 7 hepatitis.

From the skin and subcutaneous tissues: very rarely - angioedema, Stevens-Johnson syndrome; frequency unknown - toxic epidermal necrolysis, erythema multiforme.

From the musculoskeletal system and connective tissue: very rarely - rhabdomyolysis.

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

Pregnancy, postpartum and nerinal conditions: the frequency is unknown - withdrawal syndrome in newborns30.

From the genitals and the breast: infrequently - sexual dysfunction; rarely - priapism, galactorrhea, swelling of the mammary glands, disorders of the menstrual cycle.

General disorders and disorders at the injection site: very often - withdrawal syndrome 2, 31; often - slightly expressed asthenia, peripheral edema, irritability, fever; rarely - malignant neuroleptic syndrome, 2 hypothermia.

Laboratory and instrumental data: rarely - increased activity of CK in blood plasma32.

QT interval prolongation, ventricular arrhythmia, sudden death, cardiac arrest and bidirectional ventricular tachycardia are considered undesirable events inherent in neuroleptics.

Children and adolescents (10 to 17 years)

Children and adolescents may develop the same unwanted drug reactions (NLR) as in adult patients. Below are the NLRs that were not observed in adult patients or were more frequent in children and adolescents (10-17 years) than in adult patients.

The frequency of unwanted reactions is given in the form of the following gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000); frequency is unknown (can not be estimated from available data).

On the part of the endocrine system: very often - an increase in the concentration of prolactin.

From the side of metabolism and nutrition: very often - increased appetite.

From the nervous system: very often - EPS15; often - a syncope.

From the side of the vessels: very often - an increase in AD35.

From the respiratory system, chest and mediastinum: often - rhinitis.

From the digestive tract: very often - vomiting.

General disorders and disorders at the injection site: often - irritability34.

1 Reduction in Hb ≤13 g / dL in males and ≤12 g / dL in females, at least once, was noted in 11% of patients on quetiapine in all clinical trials, including long-term therapy. The average maximum reduction in Hb was 1.5 g / dL, as determined at any time.

2 See "Special instructions".

3 Based on potentially clinically significant deviations from the baseline normal level noted in all clinical trials. Reducing the number of leukocytes ≤3 · 109 / l when determining at any time.

4 Based on potentially clinically significant deviations from the baseline normal level noted in all clinical trials. An increase in the number of eosinophils ≥1 · 109 / L when determined at any time.

5 Decrease in the number of platelets ≤100 · 109 / l, at least for a single determination.

6 Based on frequency estimates in patients participating in all clinical trials of quetiapine who experienced severe neutropenia (<0.5 · 109 / L) in combination with infections (see "Specific guidance").

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

8 Increased 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.

9 Based on potentially clinically relevant deviations from the baseline observed in all clinical trials. Changes in the concentration of total and free T4, total and free T3 to values <80% of NGN (pmol / L) for determination at any time. The change in the concentration of TSH> 5 mIU / l when determined at any time.

10 See Pharmacodynamics.

11 Increased TG concentrations ≥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 In some patients, clinical deterioration in more than one metabolic factor has been observed in clinical studies: body weight, glucose concentration, and plasma lipids (see "Specific guidance").

13 Increase in the total Xc concentration ≥240 mg / dl (≥6.2664 mmol / L) in patients ≥18 years of age or ≥200 mg / dl (≥5,172 mmol / L) in patients <18 years of age, at least once. Very often an increase in LDL cholesterol ≥30 mg / dl (≥0.769 mmol / l) was noted, with an average of 41.7 mg / dl (≥1.07 mmol / l).

14 Reduction in HDL-C concentration <40 mg / dL (<1.03 mmol / L) in men and <50 mg / dl (<1.29 mmol / L) in women.

15 Increasing the initial body weight by 7% or more. It mainly occurs at the beginning of therapy in adults.

16 Increase in fasting plasma glucose ≥126 mg / dl (≥7 mmol / l) or post-prandial glucose concentration ≥200 mg / dL (≥11.1 mmol / L), at least once.

17 Change in concentration from> 132 mmol / l to ≤132 mmol / l, at least for a single determination.

18 The estimated frequency of this adverse reaction was based on reports of metabolic syndrome in all clinical trials using quetiapine.

19 Suicidal behavior and suicidal thoughts were noted during quetiapine therapy or shortly after discontinuation of therapy.

20 Like other antipsychotics with α1-adrenergic blocking action, quetiapine often causes orthostatic hypotension, which is accompanied by dizziness, tachycardia, and in some cases - fainting, especially at the onset of therapy (see "Special instructions").

21 May cause a fall.

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

23 These phenomena are often observed in the background of tachycardia, dizziness, orthostatic hypotension and / or concomitant pathology of the cardiovascular or respiratory system.

24 See below for instructions.

25 The frequency of the QTc interval change from <450 ms to ≥450 ms with an increase of ≥30 ms. 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.

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

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

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

29 There may be an asymptomatic increase (≥3 times from IGN at any time) of the activity of AST, ALT and GGT in the blood serum, usually reversible against the background of continued use of quetiapine.

30 See "Application in pregnancy and lactation".

31 In the study of withdrawal 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 quetiapine was discontinued.

32 Without communication with malignant neuroleptic syndrome. According to clinical studies.

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

34 Corresponds to the frequency observed in adult patients, but may be associated with a variety of clinical manifestations in children and adolescents, unlike in adult patients.

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

Interaction

Caution should be exercised while using Kventiax ® with other drugs that affect the central nervous system, as well as with alcohol.

Caution should be exercised in patients taking other antagonists of cholinergic (muscarinic) receptors.

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

When quetiapine therapy is not recommended to eat grapefruit juice.

In a pharmacokinetic study, the use of quetiapine at various dosages prior to or concomitant with carbamazepine administration resulted in a significant increase in quetiapine clearance and, accordingly, a 13% reduction in AUC compared with quetiapine alone without carbamazepine. In some patients, the decrease in AUC was even more pronounced. This interaction is accompanied by a decrease in the concentration of quetiapine in plasma and may reduce the effectiveness of quetiapine therapy. The simultaneous use of quetiapine with phenytoin, another inducer of microsomal liver enzymes, was accompanied by an even more pronounced (about 450%) increase in quetiapine clearance. The use of quetiapine by patients receiving inducers of microsomal liver enzymes is possible only if the expected benefit from quetiapine therapy exceeds the risk associated with the cancellation of the drug - the inductor of microsomal liver enzymes. The change in the dose of drugs - inducers of microsomal enzymes of the liver 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 (inhibitor of the isoenzyme CYP2D6) or fluoxetine (inhibitor of isoenzymes CYP3A4 and CYP2D6).

The pharmacokinetics of quetiapine does not change significantly when used concomitantly 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.

The pharmacokinetics of lithium preparations does not change with the simultaneous use of quetiapine.

When quetiapine was used with lithium drugs in adults with acute manic episodes, a higher incidence of unwanted reactions associated with EPS (especially tremor), drowsiness and weight gain was noted compared to patients taking quetiapine from placebo in a 6-week randomized trial .

There were no clinically significant changes in the pharmacokinetics of valproic acid and quetiapine, while concomitant administration of valproate semetriya and quetiapine.

A retrospective study involving children and adolescents who received sodium valproate and quetiapine alone or both simultaneously showed a higher incidence of leukopenia and neutropenia in the combination therapy group compared to the monotherapy group.

Pharmacokinetic studies on the interaction of the drug Kventiax ® with drugs used in cardiovascular disease have not been conducted.

Caution should be exercised while using quetiapine and drugs that can cause electrolyte imbalance and prolong the QTc interval.

In patients taking quetiapine, false-positive results of screening tests for the detection of methadone and tricyclic antidepressants by the enzyme immunoassay were observed. To confirm the results of screening, a chromatographic study is recommended.

With a single admission of 2 mg of lorazepam against quetiapine 250 mg twice daily, the clearance of lorazepam is reduced by approximately 20%.

Quetiapine did not induce the induction of microsomal liver enzymes involved in the metabolism of phenazone.

Dosing and Administration

Inside, 2 times a day, regardless of food intake.

Treatment of schizophrenia. The daily dose for the first 4 days of therapy is: 1st day - 50 mg; The 2nd day - 100 mg; The third day is 200 mg and the fourth day is 300 mg. Starting from the fourth day, the dose should be selected up to an effective dose, usually in the range of 300-400 mg / day. Depending on the clinical effect and the tolerability of the drug, its dose can individually vary from 150 to 750 mg / day. The maximum daily dose for the treatment of schizophrenia is 750 mg.

Treatment of manic episodes in the structure of bipolar disorder. The drug Kventiax ® is recommended as a monotherapy or in combination with drugs that have a normotimic effect. The daily dose for the first 4 days of therapy is: 1st day - 100 mg; 2nd day - 200 mg; The third day is 300 mg and the fourth day is 400 mg. An increase in the daily dose in the future is possible at 200 mg / day, and by the 6th day of therapy it will be 800 mg. Depending on the clinical effect and the tolerability of the drug, its dose can individually vary from 200 to 800 mg / day. As a rule, the effective dose is from 400 to 800 mg / day. The maximum daily dose for this indication is 800 mg.

Treatment of depressive episodes in the structure of bipolar disorder. The drug Kventiax ® is prescribed once a day for the night. The daily dose for the first 4 days of therapy is: 1st day - 50 mg, 2nd day - 100 mg, 3 days - 200 mg, 4th day - 300 mg. The recommended daily dose is 300 mg. The maximum recommended daily dose of Kventiax ® is 600 mg.

The antidepressant effect of quetiapine was confirmed when applied at a dose of 300 and 600 mg / day.

The intake of doses exceeding 300 mg should be started under the supervision of a physician with experience in the therapy of bipolar disorders. In individual patients, if there is a suspicion of poor drug tolerance, according to the results of clinical studies, it is possible to reduce the dose to a minimum of 200 mg / day.

Special patient groups

Elderly age. The drug Kventiax ®, like other antipsychotics, should be used with caution in elderly patients, especially at the beginning of therapy. The dose should be titrated more slowly, the daily therapeutic dose should be lower than in younger patients, depending on the clinical response and individual tolerability. The average clearance for quetiapine was reduced by 30-50% in elderly patients compared with younger patients. Efficacy and safety have not been studied in patients older than 65 years with depressive episodes in the structure of bipolar disorder.

Renal failure. Correction of the dose is not required.

Liver failure. Quetiapine is extensively metabolized in the liver. Therefore, care should be taken when using Kventiax ® 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 it daily by 25-50 mg until an effective dose is reached.

Overdose

Symptoms: mainly due to the enhancement of known pharmacological effects of quetiapine, such as drowsiness and sedation, tachycardia, lowering of blood pressure and anticholinergic effects.

Overdose can lead to lengthening of the QT interval, convulsive seizures, epileptic status, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and / or agitation, coma and death.

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

Treatment: it is recommended to carry out activities aimed at maintaining the function of respiration and CAS, ensuring adequate oxygenation and ventilation. There are no specific antidotes of quetiapine. In cases of severe intoxication, one should remember about the possibility of an overdose with several medications.

Reports on the resolution of severe adverse effects from the central nervous system have been published, incl. coma and delirium, after intravenous injection of physostigmine (at a dose of 1-2 mg) under constant ECG monitoring. Such treatment is not recommended as a standard treatment because of the potential adverse effect of physostigmine on cardiac conduction. The use of physostigmine is possible only in the absence of abnormalities in the ECG parameters. Do not use physostigmine in case of cardiac rhythm disturbance, blockage of any degree or with the expansion of the QRS complex.

In case of refractory arterial hypotension in quetiapine overdose, treatment should be carried out by intravenous fluids and / or sympathomimetic drugs (epinephrine and dopamine should not be given, as stimulation of β-adrenoceptors can cause an increase in blood pressure lowering with the blockade of α-adrenoreceptors 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.

Special instructions

Since the Kventiax ® preparation has several indications for use, its safety profile is determined depending on the patient's diagnosis and the dose of the drug.

Children and adolescents (10 to 17 years)

The Kventiax ® preparation 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 unwanted reactions (increased appetite, increased serum prolactin concentration, vomiting, rhinitis and syncope) in children and adolescents were observed more frequently than in adult patients, or had other clinical manifestations (EPS and irritability). 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 of quetiapine (more than 26 weeks) has not been studied.

In placebo-controlled studies in children and adolescents with schizophrenia and mania in the structure of bipolar disorder, the incidence of EPS was higher with quetiapine compared with placebo.

Suicide / suicidal thoughts or clinical worsening

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

Patients (especially those at high risk for suicide) and their caregivers should be alerted to the need to monitor clinical impairment, suicidal behavior or thoughts, an unusual change in behavior and the need to immediately consult a doctor if they occur.

According to data from short-term placebo-controlled clinical trials in patients with depression in bipolar disorder, the risk of suicidal events was 3% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18- 24 years, 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo in patients older than 25 years.

Other mental disorders for which quetiapine is administered are 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. A meta-analysis of placebo-controlled studies of antidepressants by the FDA (FDA), 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 in children, adolescents and adults under 25 years of age. This meta-analysis does not include studies where quetiapine was used (see Pharmacodynamics).

According to short-term placebo-controlled studies for all indications and in all age groups, the incidence of events associated with suicide was 0.8% for both quetiapine (76/9327) and placebo (37/4845).

In these studies in schizophrenic patients, the risk of suicidal events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients aged 18-24 years; 0.8% (13/1663) for quetiapine and 1.1% (5/463) for placebo in patients older than 25 years; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under 18 years of age.

In patients with mania in bipolar disorder, the risk of suicidal events was 0% (0/60) for quetiapine and 0% (0/58) for placebo in patients aged 18-24 years; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients older than 25 years; 1% (2/193) for quetiapine and 0% (0/90) for placebo in patients under 18 years of age.

Metabolic disorders

Given the risk of deterioration in the metabolic profile, including changes in body weight, plasma glucose and lipid concentrations noted in clinical trials, the metabolic parameters of patients should be evaluated at the beginning of therapy and monitored regularly during therapy. If these indicators worsen, appropriate treatment should be undertaken.

EPS

An increase in the incidence of EPS when taking quetiapine in adults with a large depressive episode in the structure of bipolar disorder or major depressive disorder compared with placebo was noted (see "Side effects").

The use of quetiapine was associated with the development of akathisia, which was characterized by subjectively unpleasant anxiety or anxiety and was often accompanied by an inability to sit or stand still. Such phenomena are most often observed in the first few weeks of treatment. Increasing the dose to patients who develop such symptoms may have a negative 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. Symptoms of tardive dyskinesia may increase or even occur after discontinuation of the drug (see "Side effects").

Drowsiness and dizziness

During therapy with quetiapine, drowsiness and related symptoms, for example sedation (see "Side effects"), may be noted. In clinical studies involving patients with depression in the structure of bipolar disorder and with a depressive episode, drowsiness usually developed during the first 3 days of therapy.

The severity of this undesirable reaction was mostly mild or moderate. With the development of severe drowsiness, patients with depression in the structure of bipolar disorder and patients with a depressive episode may need more frequent visits to the doctor within 2 weeks from the onset of drowsiness or to a decrease in the severity of symptoms. In some cases quetiapine therapy may be discontinued.

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

Cardiovascular diseases

Care should be taken when applying quetiapine in patients with cardiovascular, cerebrovascular diseases and other conditions predisposing to arterial hypotension. In such patients, dose selection should be slower. On the background of quetiapine therapy, orthostatic hypotension may occur, especially during dose selection at the beginning of therapy. When orthostatic hypotension occurs, a dose reduction or more gradual selection may be required.

Sleep apnea syndrome

Patients taking quetiapine showed sleep apnea syndrome. In patients taking concomitant medications, depressing the central nervous system, or having history of sleep apnea (eg, overweight / obese patients, male patients), quetiapine should be used with caution.

Convulsive seizures

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

Malignant neuroleptic syndrome

Against the background of taking antipsychotic drugs, incl. quetiapine, can develop malignant neuroleptic syndrome (see "Side effects"). Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, lability in the autonomic nervous system, increased activity of CK. In such cases, quetiapine should be withdrawn and treated accordingly.

Severe neutropenia and agranulocytosis

In the short-term placebo-controlled clinical trials of quetiapine monotherapy, cases of severe neutropenia (neutrophil count <0.5 · 109 / L) without infection were infrequent. Agranulocytosis (severe neutropenia associated with infections) has been reported in patients who received quetiapine as part of clinical trials (rarely), as well as post-marketing use (including fatal). Most of these cases of severe neutropenia occurred within 2 months after initiation of quetiapine therapy. There was no dose-response effect. Leukopenia and / or neutropenia were resolved after quetiapine therapy was discontinued. A possible risk factor for the onset of neutropenia is a previous reduced number of leukocytes and cases of drug-induced neutropenia in the anamnesis. The development of agranulocytosis was also noted in patients without risk factors. It is necessary to take into account the possibility of developing neutropenia in patients with infection, especially in the absence of obvious predisposing factors, or with unexplained fever, these cases should be conducted in accordance with clinical recommendations.

In patients with a neutrophil count <1 · 109 / L, quetiapine should be discontinued. The patient should be observed to identify possible symptoms of infection and control the amount of neutrophils (up to an increase in their number to 1.5.109 / L).

Patients should immediately report the appearance of signs / symptoms of agranulocytosis or infection (eg, fever, weakness, lethargy, sore throat) throughout the course of therapy with Kventiax ®.

Anticholinergic (antimuscarinic) effects

Norquetiapine, an active metabolite of quetiapine, exhibits moderate or high affinity for several subtypes of muscarinic receptors, which explains the development of NLR due to anticholinergic action with quetiapine at recommended doses, with simultaneous use of other anticholinergic drugs, and overdose. Caution should be exercised when using quetiapine in patients taking antagonists of cholinergic (muscarinic) receptors, as well as in patients with urinary retention, incl. in the history, clinically significant hypertrophy of the prostate gland, intestinal obstruction or associated conditions, with an increase in IOP or angle-closure glaucoma.

Interaction with other drugs

Also see "Interaction".

The simultaneous use of quetiapine with powerful inducers of microsomal liver enzymes, such as carbamazepine and phenytoin, helps to reduce the concentration of quetiapine in blood plasma and may reduce the effectiveness of therapy with Kventiax ®.

The use of Kventiax ® in patients receiving inductors of microsomal liver enzymes is possible only if the expected benefit from therapy with the drug exceeds the risk associated with the cancellation of inducers of microsomal liver enzymes. The change in the dose of drugs - inducers of microsomal enzymes of the liver should be gradual. If necessary, they can be replaced with drugs that do not induce microsomal liver enzymes (for example, preparations of valproic acid).

Body mass

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

Hyperglycaemia

Against the background of taking quetiapine may develop hyperglycemia and / or development and exacerbation of diabetes mellitus, sometimes accompanied by the development of ketoacidosis or coma, incl. with a lethal outcome. In some cases, a previous increase in body weight was noted, which may be a predisposing factor. Regular monitoring of body weight and symptoms of hyperglycemia, such as polydipsia, polyuria, polyphagia and weakness, is recommended in patients taking antipsychotics, incl. quetiapine. Clinical observation of patients with diabetes mellitus, patients with risk factors for the development of diabetes mellitus is recommended (see "Side effects").

Concentration of lipids

Against the background of taking quetiapine may increase the concentration of TG, total Xc and Xc LDL, as well as a decrease in the concentration of HDL in the blood plasma (see "Side effects"). These changes should be adjusted in accordance with the current recommendations.

QT interval extension

There was no correlation between the intake of quetiapine and the steady increase in the absolute value of the QT interval. However, prolongation of the QT interval was noted with the use of quetiapine in therapeutic doses and with an overdose of quetiapine (see "Overdose"). Caution should be exercised when using quetiapine, as well as other antipsychotics, in patients with cardiovascular disease and with a prolonged QT interval in the anamnesis. Caution should also be exercised when using quetiapine concomitantly with QTc-prolonging drugs, other antipsychotics, especially in elderly patients, patients with congenital prolongation of the QT interval, CHF, myocardial hypertrophy, hypokalemia, or hypomagnesemia (see "Interaction").

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.

Acute reactions associated with drug withdrawal

With the abrupt withdrawal of quetiapine, the following acute reactions (withdrawal syndrome) can occur: nausea, vomiting, insomnia, headache, dizziness and irritability. Therefore, the cancellation of Kventiax ® is recommended to be carried out gradually, for at least 1 or 2 weeks.

Older patients with dementia

Kventiax ® is not indicated for the treatment of psychoses associated with dementia.

Some atypical antipsychotics in randomized placebo-controlled trials increased the risk of developing cerebrovascular complications in patients with dementia approximately 3-fold. The mechanism of this increase in risk has not been studied. A similar risk of increasing the incidence of cerebrovascular complications can not be ruled out for other antipsychotic drugs or other groups of patients. The drug Kventiax ® should be used with caution in patients at risk of stroke.

Analysis of the use of atypical antipsychotics for the treatment of psychoses associated with dementia in elderly patients revealed an increase in the mortality rate in the group of patients receiving drugs of this group, compared with the placebo group. Two 10-week, placebo-controlled trials of quetiapine in a similar group of patients (n = 710, mean age 83 years, age range 56-99 years) showed that mortality in the quetiapine group was 5.5%, and 3.2% in the placebo group. The causes of deaths noted 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.

Dysphagia

Dysphagia (see "Side effects") and aspiration were observed with quetiapine therapy. The causal relationship between the onset of aspiration pneumonia and the administration of quetiapine has not been established. However, caution should be exercised when using Kventiax ® in 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 "Side effects"), including cases with fatal outcome in patients at high risk of intestinal obstruction, incl. receiving multiple concomitant medications that reduce intestinal motility, even in the absence of complaints of constipation. Patients with intestinal obstruction / ileus need urgent measures and careful monitoring.

VTE

Against the background of taking antipsychotics, cases of VTE occur. Before and during therapy with antipsychotic drugs, incl. quetiapine, should assess the risk factors and take preventive measures.

Pancreatitis

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

Disorders from the side of the liver

If jaundice develops, quetiapine should be discontinued.

Additional Information

Data on the simultaneous use of quetiapine with divalproex or lithium on the background of acute moderate or severe manic episodes are limited. A good tolerability of this combination therapy and an additive effect for 3 weeks of treatment were noted.

Special information on excipients

The preparation Kventiax ® contains lactose, therefore it should not be used in the following conditions: lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Influence on the ability to carry out potentially dangerous activities requiring special attention and quick reactions (for example, vehicle management, working with moving mechanisms)

The drug Kventiax ® can cause drowsiness, so during the treatment patients are not recommended to work with mechanisms that require increased concentration of attention, including. it is not recommended to drive vehicles.

Release form

Film-coated tablets, 100 mg, 200 mg and 300 mg. For 10 tab. in the blister (contour cell packaging). At 6 bl. in a cardboard box.

Conditions of leave from pharmacies

On prescription.

Storage conditions of the drug Kventiax

At temperatures not higher than 30 ° C.

Keep out of the reach of children.

Shelf life of the drug Kventiax

5 years.

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

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