Kvetiron

General characteristics. Structure:

Active ingredient: a kvetiapina of a fumarat in terms of кветиапин 25 mg, 100 mg or 200 mg;

Excipients: lactoses monohydrate, calcium гидрогенфосфат the dihydrate, cellulose microcrystallic, sodium krakhmalglikolit, povidone, magnesium stearate; cover: Opadry II White (Kvetiron 25, Kvetiron 200) (polyethyleneglycol, polyvinyl alcohol, talc, titanium E 171 dioxide), Opadry II Yellow (Kvetiron 100) (polyethyleneglycol, polyvinyl alcohol, talc, titanium E 171 dioxide, quinolinic yellow E 104, ferrous oxide yellow E 172, ferrous oxide red E 172).

Pharmacological properties:

Pharmacodynamics. Kvetiron - the atypical antipsychotic drug interacting with various types of neyrotransmitterny receptors. Kvetiapin has higher affinity to receptors of serotonin (5-HT2), than to receptors of a dopamine (D1 and D2) in a brain, has high affinity to histamine and to the alfa1-adrenoceptors which however were less expressed by affinity to alfa2-adrenoceptors. Influence of a kvetiapin on receptors 5-HT2 and D2 lasts to 12 h that is confirmed by data of positron emission tomography. Kvetiapin has no affinity to M-holinoretseptoram and benzodiazepine receptors. Kvetiron shows the expressed antipsychotic activity.
When studying extrapyramidal symptoms in an experiment it was established what кветиапин causes only a weak katalepsy at introduction in a dose which effectively blocks dopamine D2 receptors. Kvetiapin causes the selection decrease of the activity mesolimbic A10 of dopaminergic neurons in comparison with A9 nigrostrialny motor neurons. Frequency of development of extrapyramidal symptoms at use of a kvetiapin in doses from 75 to 750 mg/days did not differ from that at use of placebo or anticholinergic drugs.
Kvetiapin does not cause increase in level of prolactin in blood serum.

Pharmacokinetics. At intake кветиапин it is well soaked up and actively metabolized. Meal has no significant effect on bioavailability of drug. The main metabolites have no the expressed pharmacological activity. The elimination half-life makes about 7 hours. About 83% of a kvetiapin contact proteins of a blood plasma. Drug keeps efficiency at reception 2 times a day.
The pharmacokinetics of a kvetiapin linear, distinctions of pharmacokinetics of drug at men and women does not exist. Average clearance of a kvetiapin at patients advanced age is 30-50% less, than patients have 18-65 years. The clearance of a kvetiapin is reduced by 25% at patients with heavy renal failures (clearance of creatinine less than 30 ml/min.) and at patients with damages of a liver (the compensated alcoholic cirrhosis). Less than 5% of a kvetiapin are not metabolized and removed in not changed look. About 73% of a kvetiapin are excreted with urine and 21% - with a stake. Key enzyme of metabolism of a kvetiapin is CYP 3A4. Kvetiapin and some of his metabolites possess a weak inhibiting effect on P450 cytochrome enzymes - 1A2, 2C9, 2C19, 2D6 and 3A4, however only in concentration at 10-50 times of higher, than that which is reached at use of usual doses (300-450 mg/days). In vitro is not established ability of a kvetiapin to cause considerable inhibition of activity of P450 cytochrome and to influence metabolism of other medicines.

Indications to use:

- Schizophrenia.
- The maniacal episodes connected with bipolar disorder.

Route of administration and doses:

Kvetiron adults take a pill inside 2 times a day during food or between meals. The dose of drug and duration of a course of treatment are defined by the doctor individually for each patient depending on indications and severity of a disease.

Adults.
Course treatment of schizophrenia.

In the first 4 days of therapy the daily dose makes: the 1st day - 50 mg, the 2nd day - 100 mg, the 3rd day - 200 mg, the 4th day - 300 mg. Since 4th days the dose is raised to achievement of necessary clinical effect (ranging from 300 to 450 mg/days). Depending on clinical performance and portability of drug the daily dose of Kvetiron can make from 150 mg to 750 mg.
The maximum daily dose of Kvetiron for treatment of schizophrenia - 750 mg.
Course treatment of the maniacal episodes associated with bipolar disorders.
The daily dose in the first 4 days of treatment makes: the 1st day - 100 mg, the 2nd day - 200 mg, the 3rd day - 300 mg, the 4th day - 400 mg. Further the dose is raised (but no more than on 200 mg daily) to 800 mg/days, since 6th day of treatment. Depending on clinical performance and portability of drug the dose can make from 200 to 800 mg/days.
The maximum daily dose of Kvetiron for treatment of maniacal episodes - 800 mg.

To people of advanced age.
Kvetiron appoint with care, especially at the beginning of a course of treatment. For patients of this group the initial dose should not exceed 25 mg/days. The dose should be raised on 25-50 mg daily to achievement of an effective dose which should not exceed that for young patients.

Abnormal liver function and kidneys.
Kvetiapin is actively metabolized in a liver therefore Kvetiron has to be applied with care to patients with a liver failure, especially during an initial stage of administration of drug.

At patients with a renal failure or a liver at oral administration the clearance of a kvetiapin decreases approximately by 25%.
Patients with a renal or liver failure should begin 25 mg/days with a dose. The dose increases daily by 25-50 mg/days before achievement of an effective dose, depending on the clinical answer and portability of drug the patient.

Features of use:

Use during pregnancy or feeding by a breast.
Safety and efficiency of drug during pregnancy are not established therefore Kvetiron it is necessary to appoint only when the expected advantage for mother exceeds possible risk for a fruit. Drug withdrawal symptoms at newborns whose mothers accepted кветиапин during pregnancy were observed. Therefore, careful control of a condition of the newborn is necessary.
Degree of excretion of a kvetiapin in breast milk is not established therefore it is necessary to suspend feeding by a breast during treatment by drug.

Children. The data on safety and efficiency of a kvetiapin testifying in favor of drug use to children are not enough therefore Kvetiron do not apply in pediatric practice.

Cardiovascular diseases.
With extra care appoint drug to patients with cardiovascular and cerebrovascular diseases, and other states leading to arterial hypotension.
Kvetiapin can cause orthostatic hypotension, especially at the beginning of titration of a dose. In such cases the dose decline or its longer titration is necessary. It is more often observed at patients of advanced age, than at young people and can provoke accidental injuries.
In researches the interrelation of use of a kvetiapin with permanent increase in an interval of QT is not revealed. However, as well as at use of other antipsychotic drugs, it is necessary to appoint кветиапин along with the drugs extending an interval of QT and also with neuroleptics with care, to especially elderly patients, patients with an inborn syndrome of the extended QT interval, congestive heart failure, a heart hypertrophy, a hypopotassemia or a hypomagnesiemia. It is also necessary to adhere to care at purpose of a kvetiapin to patients with cardiovascular diseases or the extended QT interval in the family anamnesis.

Convulsive attacks.
As well as at use of other antipsychotic drugs, it is recommended to be careful at treatment of patients with existence of convulsive attacks in the anamnesis.

Extrapyramidal symptoms.
In researches use of a kvetiapin was associated with development of extrapyramidal symptoms, such as the akathisia characterizing subjectively unpleasant a distress by concern and need to move that is followed by inability not movably to sit or stand. Such symptoms more likely can be observed within the first several weeks of treatment. Increase in a dose to such patients can do much harm them.

Late dyskinesia.
Prolonged use of Kvetiron, as well as other antipsychotic means, can cause late dyskinesia. At emergence of symptoms of late dyskinesia it is necessary to lower a dose or to stop further treatment by Kvetiron.

Malignant antipsychotic syndrome.
The malignant antipsychotic syndrome can be connected with performing antipsychotic treatment, including treatment by Kvetiron. Clinical manifestations of a syndrome include: a hyperthermia, the changed mental status, muscular rigidity, instability of the autonomic nervous system, increase in level of a kreatinfosfokinaza. In such cases treatment by Kvetiron has to be stopped and carried out a symptomatic treatment.

Suicide / suicide thoughts.
At treatment of mental disorders it is necessary to observe precautionary measures of rather suicide manifestations. Patients with suicide manifestations in the anamnesis or patients who show considerable degree of thoughts of a suicide prior to treatment have high risk of attempts of a suicide and demand careful monitoring during treatment.

Increase in risk of emergence of the events connected with a suicide is observed at patients aged up to 25 years. Besides, it is necessary to consider potential risk of emergence of the events connected with a suicide after the sharp termination of treatment kvetiapiny because of the known risk factors at a disease concerning which treatment was carried out.

Careful observation of patients and, in particular those who have high risk has to be followed by medicamentous therapy, especially in an initiation of treatment and at subsequent changes of a dosage. Patients should be warned about need of monitoring of suicide behavior or thoughts, unusual changes in behavior and the immediate request for medical care at emergence of such symptoms.

Drowsiness.
Treatment kvetiapiny is associated with drowsiness and symptoms like sedation. Such symptoms can arise during the first 3 days of treatment and happen preferential easy or moderate intensity. In certain cases observation of a condition of the patient about 2 weeks after emergence of drowsiness, or before disappearance of symptoms is necessary, or there can be a need for drug withdrawal.

Heavy neutropenia.
In researches hard cases of a neutropenia arose infrequently, in most cases within several months after an initiation of treatment kvetiapiny. There is no obvious dozozavisimost. Possible risk factors of emergence of a neutropenia include already existing leukopenia and existence in the anamnesis of medicamentally induced neutropenia. Use of a kvetiapin patients with quantity of neutrophils <1,0Õ109/l should stop. It is necessary to watch a condition of patients for identification of infection symptoms at them and to control quantity of neutrophils (so far they will not exceed 1,5Õ109/l).

Sudden termination of administration of drug.
At sharp cancellation of high doses of drug the withdrawal which is shown by sleeplessness, a headache, dizziness, nausea, vomiting, diarrhea, irritability can be observed. Cases of an aggravation of psychotic symptoms and emergence of spontaneous movements are known (akathisias, dystonias, dyskinesia). Frequency of emergence of such reactions decreased in 1 week after the treatment termination. Considering danger of development of the specified reactions, it is necessary to cancel drug gradually, at least within one-two weeks.

Hyperglycemia.
During treatment kvetiapiny it was in rare instances reported about cases of a hyperglycemia or an exacerbation of diabetes. In certain cases these phenomena arose at patients with the increased body weight that could be the contributing factor. It is recommended to carry out appropriate clinical monitoring according to the standard recommendations about use of antipsychotic means. Patients to whom treatment is carried out by any antipsychotic means including кветиапин, need observation for identification of possible signs and symptoms of a hyperglycemia (such as polydipsia, polyuria, polyphagia and weakness), and patients with a diabetes mellitus or risk factors of a diabetes mellitus - regular monitoring of glycemic control. It is necessary to control body weight also constantly.

Lipids. At use of a kvetiapin in researches growth of lipids was observed. At increase in levels of lipids it is necessary to apply the corresponding treatment.

Patients of advanced age with the psychosis connected with dementia.
Kvetiapin is not approved for treatment of the psychosis connected with dementia. In researches at patients with dementia at use of some atypical anti-psychotics increase almost by 3 times of risk of emergence of the undesirable cerebrovascular phenomena was observed. The mechanism of such increase in risk is unknown. The increased risk cannot be excluded for other anti-psychotics or for other categories of patients. Kvetiron patients should apply with care with existence of risk factors of development of a stroke.

Influence on a liver.
In case of development of jaundice Kvetiron's use should be stopped.

Dysphagy.
Kvetiapin can cause a dysphagy therefore it has to be applied with care to patients with risk of aspiration pneumonia.

Venous thromboembolism.
Against the background of reception of neuroleptics cases of a venous thromboembolism were noted. Because the patients accepting neuroleptics often have acquired risk factors of a venous thromboembolism, they need to be revealed to and during treatment by Kvetiron and to take the warning measures.

Drug contains lactose therefore to patients with such rare hereditary diseases as intolerance of a galactose, deficit of lactase of Lapp or glucose galactose malabsorption disturbance, it is not necessary to accept this drug.

Ability to influence speed of response at control of motor transport or work with other mechanisms.
Kvetiron can cause drowsiness and dizziness therefore during treatment patients are not recommended to work with dangerous mechanisms, and also to manage vehicles.

Side effects:

At Kvetiron's reception most often can be observed: sonlivost1,2,6, golovokruzheniye5,6, dryness in a mouth, an adynamy of easy degree, a lock, takhikardiya5, orthostatic gipotenziya1,5,6 and dyspepsia.
As well as at use of other antipsychotic drugs, during treatment kvetiapiny the leukopenia, peripheral hypostases are noted to a syncope, malignant antipsychotic sindrom1.
Other possible side reactions.
From blood and lymphatic system: eosinophilia, thrombocytopenia, neytropeniya1.
From immune system: hypersensitivity, anaphylactic reaction.
Mental disturbances: abnormal dreams, nightmares, suicide thoughts and behavior.
From a nervous system: headache, loss soznaniya5,6, extrapyramidal disturbances, dysarthtia, sudorogi1, epilepsy, syndrome of uneasy legs, late diskineziya1.
Cardial disturbances: lengthening of an interval of QT1.
Vascular disorders: venous thromboembolism.
From organs of sight: blurring of sight.
From respiratory system: rhinitis, short wind.
From a digestive tract: disfagiya1, vomiting.
From gepatobiliarny system: jaundice, hepatitis.
From skin and hypodermic cellulose: Quincke's disease, Stephens-Johnson's syndrome.
From a musculoskeletal system: рабдомиолиз.
From endocrine system: giperprolaktinemiya; disturbance of secretion of antidiuretic hormone.
Disbolism, metabolism: hyponatremia, diabetes mellitus.
From reproductive system and mammary glands: priapism, sexual dysfunction, galactorrhoea, swelling of mammary glands, disturbance of a menstrual cycle.
General disturbances: symptoms otmeny1, increase in appetite, increase in weight tela3, irritability.
Laboratory indicators: increase in levels of serumal transaminases (ALT, AST)4, increase in glucose of blood to giperglikemicheskikh1 levels, increase in level gamma глутамилтрансферазы (gamma GT), increase in level of triglycerides, increase in level of the general cholesterol (due to increase in lipoproteids of low density), reduction of level of lipoproteids of high density, decrease in hemoglobin, increase in level kreatinfosfokinazy7.

Notes:
1 - see the section "Features of Use"; 2 - drowsiness can be noted in the first two weeks of treatment and, as a rule, passes at prolonged use of Kvetiron; 3 - as well as at effect of other antipsychotic drugs, increase in body weight, mostly in the first weeks of treatment is possible; 4 - asymptomatic increase in levels of serumal transaminases (ALT, nuclear heating plant) or gamma GT can be observed at certain patients; 5 - as well as during treatment by other antipsychotic drugs having alpha and adrenergic activity (block alpha adrenoceptors), Kvetiron can cause the orthostatic hypotension which is shown dizziness, tachycardia, and in some patients - a loss of consciousness, especially in an initiation of treatment; 6 - can lead to falling; 7 increase in level of a kreatinfosfokinaza in blood can be connected with a malignant antipsychotic syndrome.
During treatment kvetiapiny insignificant dozozavisimy decrease in level of hormones of a thyroid gland, in particular the general and free T4 is observed. The maximum decrease in the general and free T4 is registered on 2-4 week of therapy, without further decrease in level of hormones at prolonged treatment. Practically in all cases the level of the general and free T4 was returned to initial after the therapy termination kvetiapiny, irrespective of treatment duration.
At use of neuroleptics lengthening of an interval of QT on an ECG was very seldom reported about cases, to ventricular arrhythmia, polymorphic ventricular tachycardia, sudden death, a cardiac standstill, and such effects are klasspetsifichny.

Interaction with other medicines:

Kvetiron it is necessary to apply with care in a combination with the drugs operating on the central nervous system. In this regard during treatment alcohol intake is categorically forbidden.

CYP 3A4 is key enzyme, the metabolism of a kvetiapin which is taking part in cytochrome of P450-mediated. At an interaction research at healthy volunteers combined use of a kvetiapin (25 mg) with ketokonazoly (CYP 3A4 inhibitor) led to increase in AUC of a kvetiapin by 5-8 times. Thus, combined use of a kvetiapin with CYP 3A4 inhibitors contraindicated. Also it is not recommended to use grapefruit juice during treatment kvetiapiny.

Co-administration of a kvetiapin and carbamazepine (the inductor of microsomal enzymes of a liver) leads to increase in clearance of a kvetiapin. At co-administration of a kvetiapin and Phenytoinum (or other inductors of liver enzymes, such as carbamazepine, barbiturates, rifampicin) system influence of a kvetiapin can significantly decrease, therefore there can be a need for increase in doses of a kvetiapin for preservation of control of psychotic symptomatology. The dose of a kvetiapin can be lowered at cancellation of Phenytoinum, carbamazepine or other inductors of liver enzymes or when replacing with drug which has no the inducing influence on microsomal enzymes of a liver (for example sodium Valproatum).

It is possible to begin therapy by Kvetiron for the patients accepting the inductor of liver enzyme only if the doctor considers that the advantage of Kvetiron's use prevails over the risks connected with cancellation of the inductor of liver enzyme. It is important that any changes in reception of the inductor were gradual.

The lithium pharmacokinetics at co-administration of a kvetiapin does not change.

The pharmacokinetics of Valproatum of sodium and kvetiapin at simultaneous use does not change.

The pharmacokinetics of a kvetiapin significantly does not change at co-administration with risperidony or a haloperidol. The concomitant use of a kvetiapin and thioridazine leads to increase in clearance of a kvetiapin approximately for 70%.

The pharmacokinetics of a kvetiapin significantly does not change at simultaneous use with Cimetidinum - P450 cytochrome inhibitor. Co-administration of a kvetiapin and antidepressant of Imipraminum (CYP 2D6 inhibitor) or fluoxetine (CYP 3A4 and CYP 2D6 inhibitor) does not cause significant changes of pharmacokinetics.

The interaction research with cardiovascular drugs was not conducted.

It is necessary to adhere to care at simultaneous use of a kvetiapin with medicines which break electrolytic balance or extend QT interval.

At the patients accepting кветиапин cases of false positive results of the fermental immunoanalysis on availability of methadone and tricyclic antidepressants were noted. It is recommended to check doubtful results of the screening immunoanalysis by means of a recovery hromatografichesky method.

Contraindications:

Contraindications. The increased individual sensitivity to any of drug components.
Concomitant use of inhibitors of P450 3A4 cytochrome, such as inhibitors of the PITCHFORK proteases, azolny antifungal drugs, erythromycin, кларитромицин and нефазодон.

Overdose:

Cases of administration of drugs of a kvetiapin in a dose over 30 g without lethal effects and with full clinical rehabilitation are described. However there are also messages on the isolated cases of overdose which led to lengthening of an interval of QT, a coma or death. Patients with diseases of cardiovascular system can be in group of the increased risk of effects of overdose.

Symptoms: drowsiness, sedation, tachycardia and arterial hypotension as a result of strengthening of the known pharmacological effects of drug.

Treatment: the specific antidote does not exist. In cases of the expressed intoxication it is necessary to carry out intensive symptomatic medicamentous care, and also to recover and control passability of respiratory tracts, adequate ventilation and oxygenation, activity of cardiovascular system. In case of heavy overdose the gastric lavage, but not later than in an hour after administration of drug, use of absorbent carbon is possible.
Careful medical control of a condition of the patient has to continue to his absolute recovery.

Storage conditions:

To store in original packaging in the place, unavailable to children, at a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

Kvetiron 25: on 30 tablets in the blister; on 1 blister in a pack from a cardboard.

Kvetiron 100: on 10 tablets in the blister; on 1, 3, Abo 6 blisters in a pack from a cardboard;

Kvetiron 200: on 10 tablets in the blister; on 1, 3, Abo 6 blisters in a pack from a cardboard.