Serokvel Prolong

General characteristics. Structure:

One tablet of the prolonged action, film coated 50 mg contains:
Active agent: 57,56 mg of a kvetiapin of a fumarat (50,00 mg of a kvetiapin are equivalent)
Excipients: lactoses monohydrate of 125,72 mg, cellulose of microcrystallic 125,72 mg, citrate sodium dihydrate of 36,00 mg, gipromelloza (2208) 150,00 mg, magnesium stearate of 5,00 mg; film cover: gipromelloza (2910) 7,35 mg, macrogoal of 400 2,21 mg, titanium mg E171 2,72 dioxide, dye ferrous oxide of red E172 0,11 mg, dye ferrous oxide of yellow E172 0,11 mg.
One tablet of the prolonged action, film coated 150 mg contains:
Active agent: 172,69 mg of a kvetiapin of a fumarat (150,00 mg of a kvetiapin are equivalent)
Excipients: lactoses monohydrate of 74,65 mg, cellulose of microcrystallic 74,65 mg, citrate sodium dihydrate of 71,88 mg, gipromelloza (2208) 172,50 mg, magnesium stearate of 8,63 mg; film cover: gipromelloza (2910) 9,01 mg, macrogoal of 400 1,80 mg, titanium mg E171 3,60 dioxide.
One tablet of the prolonged action, film coated 200 mg contains:
Active agent: 230,26 mg of a kvetiapin of a fumarat (200,00 mg of a kvetiapin are equivalent)
Excipients: lactoses monohydrate of 52,87 mg, cellulose of microcrystallic 52,87 mg, citrate sodium dihydrate of 75,00 mg, gipromelloza (2208) 180,00 mg, magnesium stearate of 9,00 mg; film cover: gipromelloza (2910) 8,82 mg, macrogoal of 400 2,65 mg, titanium mg E171 3,27 dioxide, dye ferrous oxide of yellow E172 0,26 mg.
One tablet of the prolonged action, film coated 300 mg contains:
Active agent: 345,38 mg of a kvetiapin of a fumarat (300.00 mg of a kvetiapin are equivalent)
Excipients: lactoses monohydrate of 49,31 mg, cellulose of microcrystallic 49,31 mg, citrate sodium dihydrate of 100,00 mg, gipromelloza (2208) 240,00 mg, magnesium stearate of 16,00 mg; film cover: gipromelloza (2910) 11,77 mg, macrogoal of 400 3,53 mg, titanium mg E171 4,66 dioxide, dye ferrous oxide of yellow E172 0,04 mg.
One tablet of the prolonged action, film coated 400 mg contains:
Active agent: 460,50 mg of a kvetiapin of a fumarat (400,00 mg of a kvetiapin are equivalent)
Excipients: lactoses monohydrate of 15,50 mg, cellulose of microcrystallic 15,60 mg, citrate sodium dihydrate of 100,00 mg, gipromelloza (2208) 261,00 mg, magnesium stearate of 17,40 mg; film cover: gipromelloza (2910) 13,63 mg, macrogoal of 400 2,73 mg, titanium mg E171 5,45 dioxide.
Description:
Tablet of 50 mg: Oblong biconvex tablet of pink color, film coated; with XR 50 engraving on one party;
Tablet of 150 mg: Oblong biconvex tablet of white color, film coated; with XR 150 engraving on one party;
Tablet of 200 mg: Oblong biconvex tablet of yellow color, film coated; with XR 200 engraving on one party;
Tablet of 300 mg: Oblong biconvex tablet of light yellow color, film coated; with XR 300 engraving on one party;
Tablet of 400 mg: Oblong biconvex tablet of white color, film coated; with XR 400 engraving on one party.

Pharmacological properties:

Pharmacodynamics. Action mechanism
Kvetiapin is atypical antipsychotic drug. Kvetiapin and his active metabolite N-dezalkilkvetiapin interact with neytrotransmitterny receptors of a brain. Kvetiapin and N-dezalkilkvetiapin show high affinity to 5HT2-serotoninovy receptors and D1-and D2 - dopamine receptors of a brain. Higher selectivity to 5HT2-serotoninovy receptors, than to D2 - dopamine receptors, causes the main clinical antipsychotic properties of the drug Serokvel® of Prolong and low frequency of development of extrapyramidal side effects. Besides, N-dezalkilkvetiapin shows high affinity to noradrenaline carrier. Kvetiapin and N-dezalkilkvetiapin have high affinity to histamine and α1-адренорецепторам and smaller affinity in relation to α2-адренорецепторам and to 5HT1-serotoninovy receptors. Kvetiapin does not show appreciable affinity to M-holino-and benzodiazepine receptors.
In standard tests at animals 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 receptors. Kvetiapin causes the selection reduction of activity of mesolimbic A10-dofaminergichesky neurons in comparison with A9-nigrostriatnymi the neurons involved in motor function.
Serokvel® Prolong is well transferred at reception in the recommended doses, including elderly patients.
At patients of an age group from 66 to 89 years with dementia administration of drug of Serokvel® Prolong in doses from 50 mg to 300 mg a day reduces depression symptoms.
Frequency of EPS and increase in body weight at stable patients with schizophrenia, does not increase at long therapy by the drug Serokvel® of Prolong.
In researches of big depressive frustration on criteria of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed.) - The reference book on diagnosis and statistics of mental disorders, the 4th edition) did not observe increase in risk of suicide behavior and suicide thinking at administration of drug of Serokvel® Prolong in comparison with placebo.
In two short-term (6 week) researches of a combination therapy of a depressive episode the drug Serokvel® of Prolong in a dose of 150 mg/days and 300 mg/days with amitriptyline, bupropiony, tsitalopramy, duloksetiny, estsitalopramy, fluoxetine, paroksetiny, sertraline or venlafaksiny at patients with the suboptimal response to monotherapy by antidepressant showed improvement of symptoms of a depression on MADRS scale (Montgomery-Asberg Depression Rating Scale, the Scale of assessment of a depression of Montgomery-Asberg) (mean square change 2-3,3 points) in comparison with monotherapy by antidepressant.

Pharmacokinetics. Kvetiapin is well soaked up from digestive tract. The maximum concentration of a kvetiapin and N-dezalkilkvetiapina in a blood plasma is reached approximately in 6 hours after administration of drug of Serokvel® Prolong. Equilibrium molar concentration of an active metabolite of N-dezalkilkvetiapina makes 35% of that of a kvetiapin.
The pharmacokinetics of a kvetiapin and N-dezalkilkvetiapina linear also has dozozavisimy character at administration of drug of Serokvel® Prolong in a dose to 800 mg once a day.
At administration of drug of Serokvel® Prolong once a day in the dose equivalent to the daily dose of the drug Serokvel® taken for two receptions observed the similar areas under a curve of dependence of concentration from time (AUC), but the maximum concentration in plasma (Cmax) was 13% less. The size AUC of a metabolite N-dezalkilkvetiapina was 18% less.
Researches of influence of meal on bioavailability of a kvetiapin showed that meal with the high content of fats leads to statistically significant increase in Cmax and AUC for the drug Serokvel® of Prolong – approximately for 50% and 20%, respectively. Meal with the low content of fats did not exert significant impact on Cmax and AUC of a kvetiapin. It is recommended to accept Serokvel® Prolong once a day separately from food.
About 83% of a kvetiapin contact proteins of a blood plasma.
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, the exceeding concentration, observed at usually used effective dose of 300-800 mg/days.
Based on results of in vitro, it is not necessary to expect that simultaneous use of a kvetiapin with other drugs will lead to clinically expressed inhibition of the metabolism of other medicines mediated by P450 cytochrome.
The elimination half-life of a kvetiapin and N-dezalkilkvetiapina makes about 7 and 12 hours, respectively. On average less than 5% of a molar dose of fraction of a free kvetiapin and N-dezalkilkvetiapina of plasma are removed with urine. About 73% of a kvetiapin are removed with urine and 21% with excrements. Kvetiapin is actively metabolized in a liver, less than 5% of a kvetiapin are not exposed to metabolism and it is removed in not changed look by kidneys or with excrements.
Distinctions of pharmacokinetic indicators at men and women are 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), but individual indicators of clearance are in limits of the values revealed at healthy volunteers.
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 dose adjustment.

Indications to use:

• Schizophrenia, including:
- Prevention of a recurrence at stable patients
• Bipolar disorders, including:
- Moderate and heavy maniacal episodes in structure of bipolar disorder
- Heavy episodes of a depression in structure of bipolar disorder
- Prevention of a recurrence of bipolar disorders at patients with the previous effective therapy kvetiapiny maniacal or depressive episodes in structure of bipolar disorder
• Depressive episode:
- A combination therapy at the suboptimal response to monotherapy by antidepressant.

Route of administration and doses:

Serokvel® Prolong should be accepted once a day on an empty stomach (at least in one hour prior to meal). Tablets need to be swallowed entirely – not to divide, not to chew and not to break.
Adults
Treatment of schizophrenia, moderate and heavy maniacal episodes in structure of bipolar disorder
It is necessary to take the drug Serokvel® of Prolong not less, than for 1 h before meal.
The daily dose for the first 2 days of therapy makes: the 1st days – 300 mg, the 2nd days – 600 mg. The recommended daily dose makes 600 mg, however if necessary can be increased to 800 mg/days. Depending on clinical effect and individual portability the patient, the dose can vary ranging from 400 to 800 mg/days. The maintenance therapy at schizophrenia does not require dose adjustment after stopping of an aggravation.
Treatment of episodes of a depression in structure of bipolar disorder
Serokvel® Prolong should be accepted before going to bed. 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 daily dose makes 300 mg. Depending on clinical effect and individual portability the dose can be increased by the patient to 600 mg. Advantage of use of the drug Serokvel® of Prolong in a daily dose of 600 mg in comparison with 300 mg is not revealed. Serokvel® Prolong in the dose exceeding 300 mg has to be appointed the doctor having experience of therapy of bipolar disorders.
Prevention of a recurrence of bipolar disorders at patients with the previous effective therapy kvetiapiny maniacal or depressive episodes in structure of bipolar disorder For prevention of a recurrence of the maniacal, depressive and mixed episodes at bipolar disorders to patients with affirmative answer on treatment by the drug Serokvel® of Prolong, it is necessary to continue therapy in the same daily dose, as well as at the beginning of therapy. Serokvel® Prolong should be accepted before going to bed. Depending on clinical effect and individual portability the patient, the dose can vary ranging from 300 to 800 mg/days. For a maintenance therapy it is recommended to use a minimal effective dose of the drug Serokvel® of Prolong.
Combination therapy of a depressive episode at the suboptimal response to monotherapy by antidepressant
Serokvel® Prolong should be accepted before going to bed. It is necessary to use a minimal effective dose, beginning therapy with 50 mg/days. The daily dose makes: the 1st and 2nd days – 50 mg, the 3rd and 4th days – 150 mg. Increase in a dose from 150 mg/days to 300 mg/days has to be based on individual assessment of a condition of the patient. When using high doses of drug the risk of emergence of by-effects increases.
Transfer from administration of drug of Serokvel® into administration of drug of Serokvel® Prolong
For convenience of reception the patients at the moment receiving fractional therapy by the drug Serokvel® can be transferred to administration of drug of Serokvel® Prolong in the dose equivalent to the general daily dose of the drug Serokvel® once a day. In some cases dose adjustment can be necessary.
Elderly patients
Also as well as other neuroleptics, Serokvel® Prolong it is necessary to apply with care at elderly patients, especially at the beginning of therapy. Elderly can have a selection of an effective dose of the drug Serokvel® of Prolong more slowly, and the daily therapeutic dose is lower, than at young patients. The average plasma clearance of a kvetiapin at elderly patients is 30-50% lower in comparison with young patients. At elderly patients the initial dose of the drug Serokvel® of Prolong makes 50 mg/days. The dose can be increased by 50 mg/day before achievement of the effective dose depending on the clinical answer and portability of drug the certain patient.
At elderly patients with a depressive episode the daily dose for the first 3 days of therapy makes 50 mg/days with increase up to 100 mg/days for the 4th days and to 150 mg/days for the 8th days. It is necessary to use a drug minimal effective dose, beginning treatment with 50 mg/days. In case of need it is possible to increase a dose of drug to 300 mg/days, but not earlier than the 22nd day of therapy.
Patients with a renal failure
For patients with a renal failure of dose adjustment it is not required.
Patients with a liver failure
Kvetiapin is intensively metabolized in a liver. Thereof it is necessary to be careful at use of the drug Serokvel® of Prolong for patients with a liver failure, especially at the beginning of therapy. It is recommended to begin therapy of the drug Serokvel® of Prolong with a dose of 50 mg/days and to increase a dose daily by 50 mg before achievement of an effective dose.

Features of use:

Drowsiness and dizziness
During therapy by the drug Serokvel® of Prolong 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 and with a depressive episode, 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 and to patients with a depressive episode 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 by the drug Serokvel® of Prolong can be required.
Against the background of therapy orthostatic hypotension and dizziness (see the section "Side effect"), usually during titration of a dose at the beginning of therapy can arise the drug Serokvel® of Prolong. Patients, especially elderly, have to be careful to avoid accidental injuries (falling).
Patients with cardiovascular diseases
It is necessary to be careful at purpose of the drug Serokvel® of Prolong to patients with cardiovascular and cerebrovascular diseases, and other states contributing to arterial hypotension. Against the background of therapy orthostatic hypotension, especially during titration of a dose at the beginning of therapy can arise the drug Serokvel® of Prolong. When developing orthostatic hypotension the dose decline or its slower titration can be required.
Dysphagy
Dysphagy (see the section "Side effect") and aspiration were observed at therapy by the drug Serokvel® of Prolong. Relationship of cause and effect of developing of aspiration pneumonia is not established with administration of drug of Serokvel® Prolong. However patients should be careful at purpose of drug with risk of developing of aspiration pneumonia.
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"). However, at therapy kvetiapiny patients with schizophrenia and a mania in structure of bipolar disorder, increase in frequency of emergence of EPS in comparison with placebo is not revealed.
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. Symptoms of late dyskinesia can amplify or even to arise after the termination of administration of drug (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 administration of drug of Serokvel® Prolong and to carry out the corresponding treatment.
The expressed neutropenia
In clinical trials of a kvetiapin cases of the expressed neutropenia were infrequently noted (quantity of neutrophils <0,5 × 109/l). The majority of cases of the expressed 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 reduced maintenance of leukocytes and cases lekarstvenno of the induced neutropenia in the anamnesis. At patients with the maintenance of neutrophils <1,0 × 109/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 number of neutrophils (before increase in their contents to 1,5 × 109/l).
Interaction with other medicines
Also see the section "Interaction with Other Medicines and Other Types of Interaction".
Use of the drug Serokvel® of Prolong in a combination with powerful 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 by the drug Serokvel® of Prolong.
Purpose of the drug Serokvel® of Prolong to the patients receiving inductors of microsomal enzymes of a liver is possible only if the expected advantage of therapy surpasses by the drug Serokvel® of Prolong the risk connected with cancellation of inductors 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).
Body weight
Against the background of reception of a kvetiapin increase in body weight is noted. Clinical observation of patients according to the accepted standards of therapy is recommended (see the section "Side effect").
Hyperglycemia
Against the background of reception of a kvetiapin development of a hyperglycemia and/or development and an aggravation of the diabetes mellitus which sometimes is followed by ketoacidosis or a coma is possible. Regular control of body weight and symptoms of a hyperglycemia, such as polydipsia, polyuria, polyphagia and weakness, at the patients accepting neuroleptics, including кветиапин is recommended. Clinical observation of patients with a diabetes mellitus, patients with risk factors of development of a diabetes mellitus is recommended (see the section "Side effect").
Concentration of lipids
Against the background of reception of a kvetiapin increase in concentration of triglycerides, the general cholesterol and holesterina-LPNP, and also decrease in concentration of LPVP in blood 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.
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 drug overdose (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 with lengthening of an interval of QT in the anamnesis. 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 and Other Types of Interaction").
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
Serokvel® Prolong 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. Serokvel® Prolong has to be applied 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 mortality in group of the patients receiving drugs of this group in comparison with group of placebo. 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 mortality 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.
Venous thromboembolism
Against the background of reception of neuroleptics cases of developing of a venous thrombembolia are noted. Prior to the beginning of and during therapy by antipsychotic drugs, including, the drug Serokvel® of Prolong, it is necessary to estimate risk factors and to take preventive measures.
Suicide / suicide thoughts or clinical deterioration
The depression 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.
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.
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 (Administration on control of foodstuff and medicines, 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").
The patients accepting the drug Serokvel® of Prolong have to be under fixed observation, especially in an initiation of treatment and at change of the mode of dosing. Patients (and the persons which are carrying out care of patients) have to be warned about need of the immediate request for medical care at clinical deterioration, emergence of suicide behavior / thoughts and unusual behavior.
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 0,9% both for a kvetiapin (61/6270), and for placebo (27/3047).
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 (see the section "Special Instructions").
Patients with a depression at bipolar disorder have a 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. Researches with participation of patients with a depression at bipolar disorder aged up to 18 years were not conducted.
Patients with a depressive episode have a risk of succession of events, connected with a suicide, made 2,1% (3/144) for a kvetiapin and 1,3% (1/75) for placebo is at patients at the age of 18-24 years; 0,6% (11/1798) for a kvetiapin and 0,7% (7/1054) for placebo for patients ≥ 25 years. Researches with participation of patients with a depressive episode aged to 18 years were not conducted.
INFLUENCE ON ABILITY TO DRIVE THE CAR AND OTHER MECHANISMS
Serokvel® Prolong can cause drowsiness therefore during treatment patients are not recommended to work with the mechanisms constituting danger including the control of vehicles is not recommended.

Side effects:

The most frequent side effects of the drug Serokvel® – drowsiness, dizziness, dryness in a mouth, slightly expressed adynamy, a lock, tachycardia, orthostatic hypotension and dyspepsia.
Administration of drug of Serokvel®, as well as other antipsychotic drugs, can be followed by increase in body weight, faints, development of a malignant antipsychotic syndrome, leukopenia, neutropenia and peripheral hypostases.
Frequency of side reactions is specified in a type of the following gradation: very often (≥1/10); often (≥1/100, <1/10); infrequently (≥1/1000, <1/100); seldom (≥1/10000, <1/1000); very seldom (<1/10000), not specified frequency.
Very often (≥1/10)
From the central nervous system: golovokruzheniye1,4,17, sonlivost2,17, headache
From digestive tract: dryness in a mouth
General frustration: syndrome of "cancellation" 1,10
Changes of laboratory and tool indicators:
increase in concentration of triglycerides in serum krovi1,11, the general cholesterol (mainly, cholesterol of lipoproteids of low density – LPNP) 1,12 in blood, decrease in concentration of LPVP1,18 cholesterol in blood, increase in weight tela9, decrease in concentration gemoglobina23
Often (≥1/100, <1/10)
From system of a hemopoiesis: leykopeniya1
From the central nervous system: dysarthtia, unusual and dreadful dreams, obmorok1,4,17, extrapyramidal simptomy1,13, increase in appetite, suicide thoughts and povedeniye1
From cardiovascular system:
takhikardiya1,4, feeling serdtsebiyeniya19, orthostatic gipotenziya1,4,17
From an organ of sight: sight illegibility
From respiratory system: rhinitis, odyshka19
From digestive tract: lock, dyspepsia, rvota21
General frustration: slightly expressed adynamy, irritability, peripheral hypostases, fever
Changes of laboratory and tool indicators:
increase in activity of hepatic transaminases (nuclear heating plant, ALT) in serum krovi3, decrease in quantity neytrofilov1,22, giperglikemiya1,7, increase in concentration of prolactin in serum krovi16, decrease in concentration of the general and free T420 in blood, decrease in concentration of the general T320 in blood, increase in concentration of TTG20 in blood
Infrequently (≥1/1000, <1/100);
From system of blood: eosinophilia
From immune system: hypersensitivity reactions
From the central nervous system: sudorogi1, syndrome of "uneasy legs", late diskineziya1,6
From digestive tract: disfagiya1,8
Changes of laboratory and tool indicators:
increase in activity of GGT in serum krovi3, trombotsitopeniya14, lengthening of an interval of QT1, 13, decrease in concentration of free T320 in blood
Seldom (≥1/10000, <1/1000)
From cardiovascular system: venous tromboemboliya1
From a liver and biliary tract: zheltukha6
From reproductive system: priapism, galactorrhoea
General frustration: malignant antipsychotic sindrom1, hypothermia
Changes of laboratory and tool indicators:
increase in activity of a kreatinfosfokinaza in krovi15
From the central nervous system: noctambulation and similar phenomena
Very seldom (<1/10000)
From immune system: anaphylactic reaktsii6
Metabolic disturbances: sugar diabet1,5,6
From a liver and biliary tract: gepatit6
From skin and hypodermic fabrics: angioneurotic otek6, Stephens-Dzhonsona6 syndrome
Not specified frequency
From system of a hemopoiesis: neytropeniya1
1. See the section "Special Instructions".
2. Drowsiness usually arises within the first 2 weeks after the beginning of therapy and is, as a rule, allowed against the background of the continuing administration of drug of Serokvel® Prolong.
3. Perhaps asymptomatic increase in activity of aspartate aminotransferase (nuclear heating plant), alaninaminotranspherase (ALT) and gamma глутамилтранспептидазы (GGT) in blood serum, as a rule, reversible against the background of the continuing administration of drug of Serokvel® Prolong.
4. As well as other antipsychotic drugs and α1-адреноблокаторы, Serokvel® Prolong often causes orthostatic hypotension which is followed by dizziness, tachycardia, in certain cases – a faint, especially at the beginning of therapy (see the section "Special Instructions").
5. Very exceptional cases of a decompensation of a diabetes mellitus are celebrated.
6. Assessment of frequency of this side effect was made on the basis of results of post-marketing observation of use of the drug Serokvel®.
7. 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.
8. Higher frequency of a dysphagy against the background of a kvetiapin in comparison with placebo was noted only at patients with a depression in structure of bipolar disorder.
9. More than 7% exceeding of initial body weight. Generally arises at the beginning of therapy.
10. When studying a syndrome of "cancellation" in short-term placebos - controlled clinical trials of the drug Serokvel® in the mode of monotherapy the following symptoms were noted: sleeplessness, nausea, headache, diarrhea, vomiting, dizziness and irritability. Frequency of a syndrome of "cancellation" significantly decreased in 1 week after the termination of administration of drug.
11. Increase in concentration of triglycerides ≥ 200 mg/dl (≥ 2,258 mmol/l) at patients ≥ 18 years or ≥ 150 mg/dl (≥ 1,694 mmol/l) at patients <18 years, at least at single definition.
12. Increase in concentration of the general cholesterol ≥ 240 mg/dl (≥ 6,2064 mmol/l) at patients ≥ 18 years or ≥ 200 mg/dl (≥ 5,172 mmol/l) at patients <18 years, at least at single definition. Increase in LPNP cholesterol of ≥30 mg/dl (≥0,769 mmol/l), on average - 41,7 mg/dl (≥1,07 mmol/l) is very often noted.
13. See further in the text of the Instruction.
14. Decrease in quantity of thrombocytes ≤ 100 × 109/l, at least at single definition.
15. Without communication with a malignant antipsychotic syndrome. According to clinical trials.
16. Increase in concentration of prolactin at patients ≥ 18 years:> 20 mkg/l (≥ 869,56 pmol/L) are at men;> 30 mkg/l (≥ 1304,34 pmol/L) are at women.
17. Can lead to falling.
18. Decrease in concentration of LPVP cholesterol <40 mg/dl is at men and <50 mg/dl are at women.
19. These phenomena often noted against the background of tachycardia, dizziness, orthostatic hypotension and/or the accompanying pathology of cardiovascular or respiratory system.
20. On the basis of potentially clinically significant deviations from initial contents noted in all clinical trials. Changes of concentration of the general thyroxine (T4), free T4, the general triiodothyronine (T3), free T3 <80% of the lower bound of norm (pmol/L) at measurement at any time. Change of concentration of thyritropic hormone (TTG)> 5 ¼îàñ/l at measurement at any time.
21. On the basis of the increased frequency of developing of vomiting at elderly patients (age ≥ 65 years).
22. In short-term clinical trials of monotherapy kvetiapiny at patients with quantity of neutrophils ≥1,5 × 109/l cases of a neutropenia (quantity of neutrophils <1,5 × 109/l) are noted at 1,9% of patients in group of a kvetiapin against 1,3% in group of placebo. Decrease in quantity of neutrophils ≥0,5, but <1,0 × 109/l was noted with a frequency of 0,2% in group of a kvetiapin and placebo. Decrease in quantity of neutrophils <0,5 × 109/l at least at single definition is noted at 0,21% of patients in group of a kvetiapin against 0% in group of placebo.
23. Decrease in concentration of hemoglobin ≤ 13 g/dl at men and ≤ 12 g/dl at women, at least at single, definition was noted at 11% of patients against the background of reception of a kvetiapin in all clinical trials, including long therapy. In short-term placebos - controlled researches decrease in concentration of hemoglobin ≤ 13 g/dl at men and ≤ 12 g/dl at women, at least at single definition, were noted at 8,3% of patients.
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.
Frequency of extrapyramidal symptoms (EPS) in short-term clinical trials at schizophrenia and a mania in structure of bipolar disorder was comparable 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 a depression in structure of bipolar disorder in group of a kvetiapin made 8,9%, in group of placebo – 3,8%. EPS frequency in short-term clinical trials of monotherapy at a depressive episode in group of the drug Serokvel® of Prolong made 5,4%, in group of placebo – 3,2%, elderly patients have 9,0% and 2,3%, respectively.
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, psikhimotorny 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, bipolar disorder and a depressive episode 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 concentration of T3 and TTG made 0,0% in group of a kvetiapin and in group of 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 hypothyroidism. 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 a reference value after the therapy termination kvetiapiny, irrespective of treatment duration. Concentration of tiroksinsvyazyvayushchy globulin (TSG) at measurement remained invariable with 8 patients.

Interaction with other medicines:

It is necessary to be careful at the combined use of the drug Serokvel® of Prolong 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. When studying on healthy volunteers combined use of a kvetiapin (in a dose of 25 mg) with ketokonazoly, CYP3A4 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 CYP3A4 cytochrome contraindicated. At therapy kvetiapiny it is not recommended to eat grapefruit juice.
In a pharmacokinetic research use of a kvetiapin in various dosage to or along with reception of carbamazepine led to substantial increase of clearance of a kvetiapin and, respectively, AUC reduction, on average, for 13%, in comparison with reception of a kvetiapin without carbamazepine. Some patients had even more expressed decrease in AUC. Such interaction is followed by decrease in concentration of a kvetiapin in plasma and can reduce efficiency of therapy by the drug Serokvel® of Prolong. Combined use 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 the drug Serokvel® of Prolong by the patients receiving inductors of fermental system of a liver is possible only if the expected advantage of therapy surpasses by the drug Serokvel® of Prolong the risk connected with cancellation of drug inductor of liver enzymes. Change of a dose of drugs inductors of microsomal enzymes has to be gradual. If necessary, their substitution by the drugs which are not inducing microsomal enzymes 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 the drug Serokvel® of Prolong with the drugs applied at cardiovascular diseases were not conducted.
It is necessary to be careful at the combined use of the drug Serokvel® of Prolong and drugs capable to cause disturbance of electrolytic balance and lengthening of an interval of QTc.
Kvetiapin did not cause induction of the hepatic fermental systems participating in phenazone metabolism.
At the patients accepting кветиапин false positive results screening tests on identification of methadone and tricyclic antidepressants were noted by method of an enzyme immunoassay. For confirmation of results of screening carrying out a hromatografichesky research is recommended.

Contraindications:

Hypersensitivity to any of drug components.
Deficit of lactase, 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 inhibitors of proteases (see the section "Interaction with Other Medicines and Other Types of Interaction")
In spite of the fact that efficiency and safety of the drug Serokvel® of Prolong at children and teenagers at the age of 10-17 years were studied in clinical trials, use of the drug Serokvel® of Prolong for patients aged up to 18 years is not shown.

With CARE: at patients with the cardiovascular and cerebrovascular diseases or other states contributing to arterial hypotension, advanced age, a liver failure, convulsive attacks in the anamnesis, risk of development of a stroke and aspiration pneumonia.
PREGNANCY AND LACTATION
Safety and efficiency of a kvetiapin at pregnant women are not established. Thereof, during pregnancy of Serokvel® Prolong it is possible to apply only if the expected advantage for the woman justifies potential risk for a fruit.
Degree of excretion of a kvetiapin with women's milk is not known. Women need to avoid feeding by a breast during administration of drug of Serokvel® Prolong.

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 post-marketing studying of drug. 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 lengthening of an interval of QTS, 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.
Treatment
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.
In case of developing of refractory arterial hypotension at overdose of a kvetiapin treatment should be performed by intravenous administration of liquid and/or sympathomimetic drugs (it is not necessary to appoint Epinephrinum and a dopamine as stimulation of β-adrenoceptors can cause strengthening of a lowering of arterial pressure against the background of blockade of α-adrenoceptors kvetiapiny))))))))))).
Gastric lavage (after an intubation if the unconscious patient) and use 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:

List B. To store at a temperature below 30 °C, in the places unavailable to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of the prolonged action, film coated, on 50 mg, 150 mg, 200 mg, 300 mg and 400 mg.
On 10 tablets in PVC the blister, on 6 blisters with the application instruction in a cardboard pack with control of the first opening Is scarlet/.
When packaging on CJSC ZIO-Zdorovye, Russia:
On 10 tablets in PVC the blister, on 6 blisters in a cardboard pack with the application instruction Is scarlet/.
On 10 tablets in PVC the blister, on 6 blisters with the application instruction in a cardboard pack with control of the first opening Is scarlet/.