Kvetiapin

General characteristics. Structure:

Active ingredient: 25 mg, 100 mg, 200 mg or 300 mg of a kvetiapin of a fumarat.

Excipients: cellulose, lactoses monohydrate, sodium carboxymethylstarch (sodium starch is glikolit, type A), K-30 povidone, talc, silicon dioxide colloid, magnesium stearate.

Film cover: [a gipromelloza – 10,800 mg, talc – 3,600 mg, titanium dioxide – 1,980 mg, a macrogoal 4000 (polyethyleneglycol 4000) – 1,620 mg] or [the dry mix for a film covering containing a gipromelloza (60%), talc (20%), titanium dioxide (11%), a macrogoal 4000 (polyethyleneglycol 4000) (9%)] – 18,000 mg.

Pharmacological properties:

Pharmacodynamics. Kvetiapin is atypical antipsychotic drug. Kvetiapin and his active metabolite N-dezalkilkvetiapin (норкветиапин) interact with a wide range of neytrotransmitterny receptors of a brain. Kvetiapin and N-dezalkilkvetiapin show high affinity to 5HT2-serotoninovy, D1-and D2 - to dopamine receptors of a brain. Antagonism to the specified receptors in combination with higher selectivity to 5HT2-serotoninovy receptors, than to D2 - dopamine receptors, causes clinical antipsychotic properties of a kvetiapin and low frequency of development of extrapyramidal side effects. Kvetiapin has no affinity to a carrier of noradrenaline and has low affinity to 5HT1A-serotoninovy receptors while N-dezalkilkvetiapin shows high affinity to both. The inhibition of a carrier of noradrenaline and partial agonizm concerning 5HT1A-serotoninovy receptors shown by N-dezalkilkvetiapinom can cause antidepressive effect of drug. Kvetiapin and N-dezalkilkvetiapin have high affinity to histamine and to alfa1-adrenoceptors and moderate affinity in relation to alfa2-adrenorenoretseptor. Besides, кветиапин does not possess or has low affinity to muskarinovy receptors while N-dezalkilkvetiapin shows moderate or high affinity to several subtypes of muskarinovy receptors.

In standard tests кветиапин shows antipsychotic activity. The specific contribution of a metabolite of N-dezalkilkvetiapina to pharmacological activity of a kvetiapin is not established.

Results of studying of extrapyramidal symptoms (EPS) at animals revealed that кветиапин causes a weak katalepsy in the doses which are effectively blocking D2 - dopamine receptors. Kvetiapin causes the selection reduction of activity mesolimbic A10 of dofaminergichesky neurons in comparison with A9 the nigrostriatny neurons involved in motor function.

Efficiency. Kvetiapin is effective in the relation of both positive, and negative symptoms of schizophrenia.

Kvetiapin is effective as monotherapy at maniacal episodes from the expressed severity moderated to. Data on prolonged use of a kvetiapin for prevention of the subsequent maniacal and depressive episodes are absent. Data on use of a kvetiapin in a combination with Valproatum of seven-sodium or drugs of lithium at maniacal episodes from the expressed severity moderated to are limited, however this combination therapy, in general, was well transferred. Besides, кветиапин in a dose of 300 mg and 600 mg it is effective at patients with bipolar disorder of I and II types from the expressed severity moderated to. At the same time efficiency of a kvetiapin at reception in a dose of 300 mg and 600 mg a day is comparable.

Kvetiapin is effective at patients with schizophrenia and a mania at administration of drug 2 times a day in spite of the fact that the elimination half-life of a kvetiapin makes about 7 hours. Influence of a kvetiapin on 5NT2-and D2 receptors continues till 12 o'clock after administration of drug.

At reception of a kvetiapin with titration of a dose at schizophrenia the frequency of EPS and the accompanying use of m-holinoblokatorov was comparable to that at placebo reception. At purpose of a kvetiapin in the fixed doses from 75 to 750 mg/days to patients with schizophrenia the frequency of emergence of EPS and need of the accompanying use of m-holinoblokatorov did not increase.

At use of a kvetiapin in doses to 800 mg/days for treatment of maniacal episodes for the expressed severity moderated to both in the form of monotherapy, and in a combination with drugs of lithium or Valproatum of seven-sodium, the frequency of EPS and the accompanying use of m-holinoblokatorov was comparable to that at placebo reception.

Pharmacokinetics. At oral administration кветиапин it is well soaked up from digestive tract and actively metabolized in a liver.

Meal significantly does not influence bioavailability of a kvetiapin. About 83% of a kvetiapin contact proteins of a blood plasma.

Equilibrium molar concentration of an active metabolite of N-dezalkilkvetiapina makes 35% of that of a kvetiapin. The elimination half-life of a kvetiapin and N-dezalkilkvetiapina makes about 7 and 12 hours respectively. The pharmacokinetics of a kvetiapin and N-dezalkilkvetiapina linear, distinctions of pharmacokinetic indicators at men and women is not observed.

The average clearance of a kvetiapin at elderly patients is 30-50% less, than at patients aged from 18 up to 65 years.

The average plasma clearance of a kvetiapin decreases approximately by 25% at patients with a heavy renal failure (clearance of creatinine less than 30 ml/min. / 1,73м2). At patients with a liver failure (the compensated alcoholic cirrhosis) the average plasma clearance of a kvetiapin is reduced approximately by 25%. As кветиапин it is intensively metabolized in a liver, at patients with a liver failure increase in plasma concentration of a kvetiapin is possible that demands correction of a dose.

On average less than 5% of a molar dose of fraction of a free kvetiapin and N-dezalkilkvetiapina of plasma are removed by kidneys. About 73% of a kvetiapin are removed by kidneys and 21% - through intestines. Less than 5% of a kvetiapin are not exposed to metabolism and is removed in not changed look by kidneys or through intestines.

It is established that CYP3A4 is a key isoenzyme of metabolism of the kvetiapin mediated by P450 cytochrome. N-dezalkilkvetiapin is formed with participation of an isoenzyme of CYP3A4.

Kvetiapin and some of his metabolites (including N-dezalkilkvetiapin) have the weak inhibiting activity in relation to isoenzymes of P450 1A2, 2C9, 2C19, 2D6 and 3A4 cytochrome, but only at concentration, at 5-50 times of the exceeding concentration, observed at usually used effective dosage of 300-800 mg/days.

Based on results of in vitro, it is not necessary to expect that co-administration of a kvetiapin with other drugs will lead to clinically expressed inhibition of the metabolism of other medicines mediated by P450 cytochrome.

Indications to use:

For treatment:
- schizophrenia;
- maniacal episodes in structure of bipolar disorder;
- depressive episodes from average to the expressed severity in structure of bipolar disorder.

Drug is not shown for prevention of maniacal and depressive episodes.

Route of administration and doses:

Kvetiapin can be applied irrespective of meal. Adults. Treatment of schizophrenia. Kvetiapin is appointed 2 times a day. The daily dose for the first 4 days of therapy makes: the 1st days - 50 mg, the 2nd days - 100 mg, the 3rd days - 200 mg, the 4th days - 300 mg. Since 4 days the dose has to be selected to effective, usually ranging from 300 to 450 mg/days. Depending on clinical effect and individual portability the patient, the dose can vary ranging from 150 to 750 mg/days. The maximum recommended daily dose makes 750 mg.

Treatment of maniacal episodes in structure of bipolar disorder. Kvetiapin is applied as monotherapy or in a combination with the drugs possessing normotimichesky action.

Kvetiapin is appointed 2 times a day. The daily dose for the first 4 days of therapy makes: the 1st days - 100 mg, the 2nd days - 200 mg, the 3rd days - 300 mg, the 4th days - 400 mg. Further, by 6th day of therapy the daily dose of drug can be increased to 800 mg. Increase in a daily dose should not exceed 200 mg a day.

Depending on clinical effect and individual portability, the dose can vary ranging from 200 to 800 mg/days. Usually effective dose makes from 400 to 800 mg/days. The maximum recommended daily dose makes 800 mg.

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

The antidepressive effect of a kvetiapin was confirmed at its use in a dose of 300 and 600 mg/days. At short-term therapy efficiency of a kvetiapin in doses of 300 and 600 mg/days was comparable (see the section "Pharmacodynamics").

Elderly. At elderly patients the initial dose of a kvetiapin makes 25 mg/days. The dose should be increased daily by 25-50 mg before achievement of an effective dose which will probably be less, than at young patients.

Patients with a renal failure. Correction of a dose is not required.

Patients with a liver failure. Kvetiapin is intensively metabolized in a liver. Therefore it is necessary to be careful at its use for patients with a liver failure, especially at the beginning of therapy. It is recommended to begin therapy kvetiapiny with a dose of 25 mg/days and to increase a dose daily by 25-50 mg before achievement of an effective dose.

Features of use:

Use at pregnancy and during breastfeeding. Safety and efficiency of a kvetiapin at pregnant women are not established. Therefore during pregnancy кветиапин it is possible to apply, only if the expected advantage for the woman justifies potential risk for a fruit.

At use of antipsychotic drugs, including the kvetiapina, in the third trimester of pregnancy, at newborns appears risk of development of side reactions of different degree of manifestation and duration, including EPS and/or a syndrome of "cancellation". It was reported about excitement, a hypertension, hypotonia, a tremor, drowsiness, respiratory a distress syndrome or feeding disturbances. In this regard it is necessary to watch a condition of newborns carefully.

Messages on excretion of a kvetiapin with breast milk are published, however degree of excretion is not established. Women need to recommend to avoid breastfeeding during reception of a kvetiapin.

Children and teenagers (aged from 10 up to 17 years). Drug кветиапин is not shown for use for children and teenagers up to 18 years in connection with insufficiency of data on use in this age group. By results of clinical trials some side effects (increase in appetite, increase in concentration of prolactin in a blood plasma and EPS) at children and teenagers observed with a bigger frequency, than at adult patients. The increase in arterial pressure which was not observed at adult patients is also noted. At children and teenagers also observed change of function of a thyroid gland.

Influence on growth, puberty, intellectual development and behavioural reactions at prolonged use (more than 26 weeks) of a kvetiapin was not studied. In placebo - controlled researches at children and teenagers with schizophrenia and a mania in structure of bipolar disorder the frequency of EPS was higher at use of a kvetiapin in comparison with placebo.

Suicide / suicide thoughts or clinical deterioration. The depression at bipolar disorder is connected with the increased risk of emergence of suicide thoughts, self-damage and a suicide (the events connected with a suicide). This risk remains until approach of the expressed remission. In view of the fact that before improvement of a condition of the patient from an initiation of treatment there can pass several weeks or more, patients have to be under fixed medical observation before improvement. According to the standard clinical experience, the risk of a suicide can increase at early stages of approach of remission.

According to clinical trials at the patients with a depression at bipolar disorder risk of succession of events connected with a suicide made 3,0% (7/233) for a kvetiapin and 0% (0/120) for placebo is at patients at the age of 18-24 years; 1,8% (19/1616) for a kvetiapin and 1,8% (11/622) for placebo for patients are more senior than 25 years.

Other mental disorders for which therapy it is appointed кветиапин are also connected with the increased risk of the events connected with a suicide. Besides, such states can be komorbidny with a depressive episode. Thus, the precautionary measures applied at therapy of patients with a depressive episode have to be accepted also at treatment of patients with other mental disorders.

At the sharp termination of therapy kvetiapiny it is necessary to take potential risk of succession of events into account, connected with a suicide.

Patients with suicide events in the anamnesis, and also the patients clearly introducing the suicide ideas before therapy treat group of the increased risk of suicide intentions and suicide attempts and have to be observed carefully in the course of treatment. The carried-out FDA (Management on sanitary inspection behind quality of foodstuff and medicines of the USA) the metaanalysis of placebo - controlled researches of antidepressants, generalizing data about 4400 children and teenagers and 7700 adult patients with mental disorders, revealed the increased risk of suicide behavior against the background of antidepressants in comparison with placebo at children, teenagers and adult patients aged up to 25 years. This metaanalysis does not include a research where it was used кветиапин (see the section "Pharmacodynamics").

According to short-term placebos - controlled researches on all indications and in all age groups the frequency of the events connected with a suicide made 0,8% both for a kvetiapin (76/9327), and for placebo (37/4845).

In these researches at the patients with schizophrenia risk of succession of events connected with a suicide made 1,4% (3/212) for a kvetiapin and 1,6% (1/62) for placebo is at patients at the age of 18-24 years; 0,8% (13/1663) for a kvetiapin and 1,1% (5/463) for patients are more senior than 25 years; For a kvetiapin and 1,3% (1/75) for placebo patients have 1,4% (2/147) aged up to 18 years.

Patients with a mania at bipolar disorder have a risk of succession of events, connected with a suicide, made 0% (0/60) for a kvetiapin and 0% (0/58) for placebo is at patients at the age of 18-24 years; 1,2% (6/496) for a kvetiapin and 1,2% (6/503) for placebo at patients are more senior than 25 years; For a kvetiapin and 0% (0/90) for placebo patients have 1,0% (2/193) aged up to 18 years.

Drowsiness. During therapy kvetiapiny drowsiness and the related symptoms, for example, sedation can be noted (see the section "Side effect"). In clinical trials with participation of patients with a depression in structure of bipolar disorder, drowsiness, as a rule, developed during the first three days of therapy. Expressiveness of this side effect generally was insignificant or moderate. At development of the expressed drowsiness more frequent visits to the doctor within 2 weeks from the moment of emergence of drowsiness can be required by patients with a depression in structure of bipolar disorder or before reduction of expressiveness of symptoms. In certain cases the therapy termination kvetiapiny can be required.

Patients with cardiovascular diseases. It is necessary to be careful at purpose of a kvetiapin to patients with serdechnoksosudisty and cerebrovascular diseases, and other states contributing to hypotension. Against the background of therapy kvetiapiny there can be orthostatic hypotension, especially during titration of a dose at the beginning of therapy. When developing orthostatic hypotension the dose decline or its slower titration can be required.

Convulsive attacks. Distinctions in the frequency of development of spasms in the patients accepting кветиапин or placebo are not revealed. However, as well as at therapy by other antipsychotic medicines, it is recommended to be careful at treatment of patients with existence of convulsive attacks in the anamnesis (see the section "Side effect").

Extrapyramidal symptoms. Increase in frequency of emergence of EPS at adult patients with a depression in structure of bipolar disorder at reception of a kvetiapin concerning depressive episodes in comparison with placebo is noted (see the section "Side effect").

Late dyskinesia. In case of development of symptoms of late dyskinesia it is recommended to lower a dose of drug or gradually to cancel it (see the section "Side effect").

Malignant antipsychotic syndrome. Against the background of reception of antipsychotic drugs, including, a kvetiapina, the malignant antipsychotic syndrome can develop (see the section "Side effect"). Clinical manifestations of a syndrome include a hyperthermia, the changed mental status, muscular rigidity, lability of the autonomic nervous system, increase in activity of a kreatinfosfokinaza. In such cases it is necessary to cancel кветиапин and to carry out the corresponding treatment.

Heavy neutropenia and agranulocytosis. In short-term placebos - controlled clinical trials of monotherapy kvetiapiny cases of a heavy neutropenia (quantity of neutrophils <0,5 x 109/l) without infection were infrequently noted. It was reported about development of an agranulocytosis (the heavy neutropenia which was associated with infections) in the patients receiving кветиапин within clinical trials (seldom) and also at post-marketing use (including with a lethal outcome).

The majority of these cases of a heavy neutropenia arose in several months after the beginning of therapy kvetiapiny. The dozozavisimy effect was not revealed. The leukopenia and/or a neutropenia was resolved after the therapy termination kvetiapiny. Possible risk factor for emergence of a neutropenia is the previous lowered quantity of leukocytes and cases lekarstvenno of the induced neutropenia in the anamnesis.

Development of an agranulocytosis was noted also at patients without risk factors. It is necessary to consider a possibility of development of a neutropenia in patients with an infection, especially in case of lack of the obvious contributing factors, or at patients with inexplicable fever; these cases have to be conducted according to clinical recommendations.

At patients with quantity of neutrophils <1,0Õ109/l reception of a kvetiapin should be stopped. The patient needs to be observed for identification of possible symptoms of an infection and to control the level of neutrophils (before exceeding of level 1,5х109/l).

Interaction with other medicines. Also see the section "Interaction with Other Medicines". Use of a kvetiapin in a combination with strong inductors of microsomal enzymes of a liver, such as carbamazepine and Phenytoinum, promotes decrease in concentration of a kvetiapin in plasma and can reduce efficiency of therapy kvetiapiny.

Purpose of a kvetiapin to the patients receiving inductors of microsomal enzymes of a liver is possible only if the expected advantage of therapy kvetiapiny surpasses the risk connected with cancellation of drug inductor of microsomal enzymes of a liver. Change of a dose of drugs inductors of microsomal enzymes of a liver has to be gradual. If necessary, their substitution by the drugs which are not inducing microsomal enzymes is possible (for example, valproic acid drugs).

Hyperglycemia. Against the background of reception of a kvetiapin development of a hyperglycemia is possible: increase in concentration of glucose of blood on an empty stomach ≥ 126 mg/dl (≥ 7,0 mmol/l) or blood glucose after meal ≥ 200 mg/dl (≥ 11,1 mmol/l) at least at single definition or a diabetes mellitus aggravation at patients with a diabetes mellitus in the anamnesis. Clinical observation of patients with a diabetes mellitus and patients with risk factors of development of a diabetes mellitus is recommended (see the section "Side effect").

Maintenance of lipids. Against the background of reception of a kvetiapin increase in concentration of triglycerides and cholesterol, and also decrease in concentration of LPVP is possible (see the section "Side effect").

Metabolic disturbances. Increase in body weight, increase in concentration of glucose and lipids in blood at some patients can lead to deterioration in a metabolic profile that demands the corresponding observation. Perhaps asymptomatic increase (≥ 3 times from the upper bound of norm at measurement at any time) activities of ALT, nuclear heating plant and GGT in a blood plasma, as a rule, reversible against the background of the continuing reception of a kvetiapin.

Lengthening of an interval of QT. The interrelation between reception of a kvetiapin and permanent increase in absolute value of an interval of QT is not revealed. However lengthening of an interval of QT was noted at overdose of a kvetiapin (see the section "Overdose"). It is necessary to be careful at purpose of a kvetiapin, as well as other antipsychotic drugs, to patients with cardiovascular diseases and earlier noted lengthening of an interval of QT. It is also necessary to be careful at purpose of a kvetiapin along with the drugs extending QTS interval, other neuroleptics, especially at elderly people, patients with a syndrome of inborn lengthening of an interval have QT, chronic heart failure, a myocardium hypertrophy, a hypopotassemia or a hypomagnesiemia (see the section "Interaction with Other Medicines"). 

The acute reactions connected with drug withdrawal. At sharp cancellation of a kvetiapin the following acute reactions (a syndrome of "cancellation") – nausea, vomiting, sleeplessness, a headache, dizziness and irritability can be observed. Therefore drug withdrawal is recommended to be carried out gradually within, at least, one or two weeks.

Elderly patients with dementia. Kvetiapin is not shown for treatment of the psychoses connected with dementia. Some atypical neuroleptics in randomized placebos - controlled researches approximately by 3 times increased risk of development of cerebrovascular complications in patients with dementia. The mechanism of this increase in risk is not studied. The similar risk of increase in frequency of cerebrovascular complications cannot be excluded for other antipsychotic medicines or other groups of patients. Kvetiapin has to be used with care at patients with risk of development of a stroke.

The analysis of use of atypical neuroleptics for treatment of the psychoses connected with dementia at elderly patients revealed increase in death rate in group of the patients receiving drugs of this group in comparison with group of placebo.

Besides, two 10 weeks placebos - the patients controlled researches of a kvetiapin at similar group (n=710; middle age: 83 years; age range: 56-99 years) showed that death rate in group of the patients accepting кветиапин made 5,5% and 3,2% in group of placebo. The reasons of the lethal outcomes noted at these patients corresponded expected for this population. Relationship of cause and effect between treatment kvetiapiny and risk of increase in mortality at elderly patients with dementia is not revealed.

Disturbances from a liver. In case of development of jaundice administration of drug Kvetiapin should be stopped.

Dysphagy. A dysphagy (see the section "Side effect") and aspiration were observed at therapy kvetiapiny. Relationship of cause and effect of developing of aspiration pneumonia is not established with reception of a kvetiapin. However, patients should be careful at purpose of drug with risk of developing of aspiration pneumonia.

Lock and impassability of intestines. The lock is risk factor of impassability of intestines. Against the background of use of a kvetiapin noted development of a lock and impassability of intestines (see the section "Side effect"), including cases with a lethal outcome at the patients of group of high risk of impassability of intestines including receiving the multiple accompanying drugs which reduce motility of intestines, even in the absence of complaints to a lock.

Pancreatitis. During clinical trials, a post-market research and post-marketing use cases of development of pancreatitis were noted, however the causal relationship is not established with administration of drug. In post-marketing messages it is specified that many patients had risk factors of development of pancreatitis, such as increase in concentration of triglycerides, cholelithiasis and alcohol intake.

Influence on ability to control of vehicles and mechanisms. Owing to impact on the central nervous system кветиапин can influence the speed of psychomotor reactions and cause drowsiness. Therefore during treatment patients are not recommended to work with the mechanisms demanding the increased concentration of attention including the control of vehicles is not recommended, individual portability of therapy will not be established yet.

Side effects:

From the central nervous system: very often - dizziness, drowsiness, a headache, extrapyramidal symptoms; often - a dysarthtia, unusual and dreadful dreams, increase in appetite; infrequently - spasms, a syndrome of uneasy legs, late dyskinesia, a syncope; seldom - noctambulation and the similar phenomena.

From digestive tract: very often - dryness in a mouth; often - a lock, dyspepsia, vomiting; infrequently - a dysphagy; seldom - impassability intestines/Ilheus.

From system of a hemopoiesis: often - a leukopenia; frequency is unknown - a neutropenia.

From cardiovascular system: often - tachycardia, orthostatic hypotension, a heart consciousness; infrequently – bradycardia.

From respiratory system: often - an asthma; infrequently – rhinitis.

From kidneys and urinary tract: infrequently – an ischuria.

From a liver and biliary tract: seldom – jaundice; very seldom – hepatitis.

From immune system: infrequently – hypersensitivity reactions; very seldom - anaphylactic reactions.

From reproductive system: seldom – a priapism, a galactorrhoea.

From skin and hypodermic fabrics: very seldom – a Quincke's disease, Stephens-Johnson's syndrome.

From an organ of sight: often - a sight illegibility.

Metabolic disturbances: very seldom - a diabetes mellitus.

Changes of laboratory and tool indicators: very often - increase in concentration of triglycerides, increase in concentration of the general cholesterol (mainly, cholesterol of lipoproteids of low density – LPNP), decrease in concentration of cholesterol of lipoproteids of the high density (LPVP), increase in body weight, decrease in concentration of hemoglobin; often - increase in activity of alaninaminotranspherase (ALT), gamma глутамилтранспептидазы (GGT), decrease in quantity of neutrophils, increase in quantity of eosinophils, a hyperglycemia, increase in concentration of prolactin in a blood plasma, decrease in concentration of the general and free T4, decrease in concentration of the general in T3, increase in concentration of thyritropic hormone (TTG); infrequently - increase in activity of aspartate aminotransferase (nuclear heating plant), thrombocytopenia, lengthening of an interval of QT, decrease in concentration of free T3; seldom - increase in activity of a kreatinfosfokinaza, an agranulocytosis.

General frustration: very often – a syndrome of "cancellation"; often – slightly expressed adynamy, irritability, peripheral hypostases, fever; seldom - a malignant antipsychotic syndrome, a hypothermia; frequency is unknown – a syndrome of "cancellation" at newborns.

Lengthening of an interval of QT, ventricular arrhythmia, sudden death, cardiac standstill and bidirectional ventricular tachycardia are considered as the side effects inherent in neuroleptics.

EPS frequency in short-term clinical trials at adult patients in structure of bipolar disorder was comparable to schizophrenia and a mania in group of a kvetiapin and placebo (patients with schizophrenia: 7,8% in group of a kvetiapin and 8,0% in group of placebo; manias in structure of bipolar disorder: 11,2% in group of a kvetiapin and 11,4% in group of placebo).

EPS frequency in short-term clinical trials at adult patients with a depression in structure of bipolar disorder in group of a kvetiapin made 8,9%, in group of placebo – 3,8%. At the same time the frequency of separate symptoms of EPS (such as akathisia, extrapyramidal frustration, a tremor, dyskinesia, dystonia, concern, involuntary reductions of muscles, psychomotor excitement and muscular rigidity), as a rule, was low and did not exceed 4% in each of therapeutic groups. In long-term clinical trials of a kvetiapin at schizophrenia and bipolar disorder at adult patients the frequency of EPS was comparable in groups of a kvetiapin and placebo.

Against the background of therapy kvetiapiny dozozavisimy decrease in concentration of hormones of a thyroid gland can be noted. Frequency of potentially clinically significant changes of concentration of hormones of a thyroid gland in short-term clinical trials for the general T4 made 3,4% in group of a kvetiapin and 0,6% in group of placebo; for free T4 – 0,7% in group of a kvetiapin against 0,1% in group of placebo; for the general T3 – 0,54% in group of a kvetiapin against 0,0% in group of placebo; for free T3 – 0,2% in group of a kvetiapin against 0,0% in group of placebo. Change of concentration of TTG is noted with a frequency of 3,2% in group of a kvetiapin and 2,7% in group of placebo. In short-term clinical trials of monotherapy the frequency of potentially clinically significant changes of T3 and TTG made 0,0% in group of a kvetiapin and placebo; for T4 and TTG made 0,1% in group of a kvetiapin against 0,0% in group of placebo. These changes are, as a rule, not connected with clinically expressed gipoteriozy. The maximum decrease in the general and free T4 is registered on the 6th week of therapy kvetiapiny, without further decrease in concentration of hormones at prolonged treatment. Practically in all cases concentration of the general and free T4 was returned to initial level after the therapy termination kvetiapiny, irrespective of treatment duration. Concentration of tiroksinnesvyazyvayushchy globulin (TSG) at measurement remained invariable with 8 patients.

Interaction with other medicines:

It is necessary to be careful at the combined use of a kvetiapin with other drugs influencing the central nervous system and also with alcohol.

The isoenzyme of P450 (CYP) cytochrome 3A4 is the main isoenzyme which is responsible for the metabolism of a kvetiapin which is carried out through system of P450 cytochrome. Healthy volunteers have a combined use of a kvetiapin (in a dose of 25 mg) with ketokonazoly, CYP3A4 isoenzyme inhibitor, led to increase in the area under a curve "concentration time" (AUC) of a kvetiapin by 5-8 times.

Therefore combined use of a kvetiapin and inhibitors of an isoenzyme CYP3A4 is contraindicated. Also it is not recommended to accept кветиапин together with grapefruit juice.

In a pharmacokinetic research with multiple dose of a kvetiapin to or along with reception of carbamazepine substantial increase of clearance of a kvetiapin and, respectively, AUC reduction, on average, for 13%, in comparison with reception of a kvetiapin without carbamazepine is shown. Some patients had even more expressed decrease in AUC. Such interaction is followed by decrease in concentration of a kvetiapin in a blood plasma and can reduce efficiency of therapy kvetiapiny. Joint purpose of a kvetiapin with Phenytoinum, other inductor of microsomal system of a liver, was followed even more expressed (approximately for 450%) by increase in clearance of a kvetiapin. Use of a kvetiapin by the patients receiving inductors of microsomal enzymes of a liver is possible only if the expected advantage of therapy kvetiapiny surpasses the risk connected with cancellation of drug inductor of microsomal enzymes of a liver. Change of a dose of drugs inductors of microsomal enzymes of a liver has to be gradual. If necessary their substitution by the drugs which are not inducing microsomal enzymes of a liver is possible (for example, valproic acid drugs).

The pharmacokinetics of a kvetiapin significantly did not change at simultaneous use of antidepressant of Imipraminum (CYP2D6 inhibitor) or fluoxetine (CYP3A4 and CYP2D6 inhibitor).

The pharmacokinetics of a kvetiapin significantly does not change at simultaneous use with antipsychotic medicines risperidony or a haloperidol. However the concomitant use of a kvetiapin and thioridazine led to increase in clearance of a kvetiapin approximately for 70%.

The pharmacokinetics of a kvetiapin significantly does not change at simultaneous use of Cimetidinum.

At a single dose of 2 mg of lorazepam against the background of reception of a kvetiapin in a dose of 250 mg 2 times a day the clearance of lorazepam decreases approximately by 20%.

The pharmacokinetics of drugs of lithium does not change at simultaneous use of a kvetiapin. Clinically significant changes of pharmacokinetics of valproic acid and a kvetiapin at combined use of Valproatum of seven-sodium and a kvetiapin are noted.

Pharmacokinetic researches on studying of interaction of a kvetiapin with the drugs used at cardiovascular diseases were not conducted.

It is necessary to be careful at the combined use of a kvetiapin and the drugs capable to cause disturbance of electrolytic balance and lengthening of an interval of QTS.

Kvetiapin did not cause induction of the microsomal enzymes of a liver participating in phenazone metabolism.

At the patients accepting кветиапин false positive results of skriningtest on identification of methadone and tricyclic antidepressants were noted by an enzyme immunoassay method. For confirmation of results of screening carrying out a hromatografichesky research is recommended.

Contraindications:

- hypersensitivity to any of drug components, including a lactose intolerance, glyukozo-galaktozny malabsorption and intolerance of a galactose;
- combined use with P450 cytochrome inhibitors, such as antifungal drugs of group of azoles, erythromycin, кларитромицин and нефазодон, and also HIV protease inhibitors (see the section "Interaction with Other Medicines");
- age up to 18 years.

With care
- at patients with the cardiovascular and cerebrovascular diseases or other states contributing to arterial hypotension;
- advanced age;
- liver failure;
- convulsive attacks in the anamnesis;
- risk of development of a stroke;
- risk of development of aspiration pneumonia.

Overdose:

It was reported about a lethal outcome at reception of 13,6 g of a kvetiapin at the patient participating in clinical trial and also about a lethal outcome after reception of 6 g of a kvetiapin at a post-market research. At the same time the case of reception of a kvetiapin in the dose exceeding 30 g without a lethal outcome is described.

There are messages on extremely exceptional cases of overdose of a kvetiapin leading to increase in QTS of an interval, death or a coma.

At patients with a serious cardiovascular illness in the anamnesis the risk of development of side effects at overdose can increase (see the section "Special Instructions").

The symptoms noted at overdose generally were a consequence of strengthening of the known pharmacological effects of drug, such as drowsiness and sedation, tachycardia and lowering of arterial pressure.

There are no specific antidotes to a kvetiapin. In cases of heavy intoxication it is necessary to remember a possibility of overdose by several medicines. It is recommended to hold the events directed to maintenance of function of breath and cardiovascular system, ensuring adequate oxygenation and ventilation. Messages on permission of heavy undesirable effects from the central nervous system, including a coma and a delirium are published, after intravenous administration of physostigmine (in a dose of 1-2 mg) under constant control of an ECG.

In case of developing of refractory hypotension at overdose kvetiapiny treatment should be performed by intravenous administration of liquid and/or spazmomimetichesky drugs (it is not necessary to appoint Epinephrinum and dopamine as stimulation of β-adrenoceptors can cause strengthening of hypotension against the background of blockade of α-adrenoceptors kvetiapiny))))))))))).

Gastric lavage (after an intubation if the unconscious patient), purpose of absorbent carbon and purgatives can promote removal of not absorbed kvetiapin, however efficiency of these measures is not studied.

Fixed medical observation has to continue before improvement of a condition of the patient.

Storage conditions:

In the place protected from light at a temperature not over 25 ºС. To store in the place, unavailable to children. Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 25 mg, 100 mg, 200 mg and 300 mg. 10, 15, 20 or 30 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. 30, 60 or 90 tablets in bank from polyethylene of high density. 1, 2 or 3 blister strip packagings on 30 tablets, 3 blister strip packagings on 20 tablets, 2, 4 or 6 blister strip packagings on 15 tablets, 3 or 6 blister strip packagings on 10 tablets or one bank together with the instruction on a medical use in a pack from a cardboard.