Pharmacological properties

Pharmacodynamics. action mechanism. therapeutic action of an aripiprazol in treatment of schizophrenia and bipolar disorder of i of type is caused by a combination of a partial agonizm concerning receptors of d2 dopamine and serotonin of a 5-ht1 and also antagonism concerning serotonin 5-ht2a receptors. it is known that aripiprazol showed antagonistic properties on animal models of dofaminergichesky hyperactivity and agonistic properties on animal models of dofaminergichesky hypoactivity. aripiprazol has high affinity of binding of in vitro concerning receptors of d2 and d3 dopamine, receptors of serotonin of a 5-ht1 and 5-ht2 and also moderate affinity concerning receptors of d4 dopamine, serotonin 5-ht2c and 5-ht7, adrenoceptors alfa1 — and h1 histamine receptors. aripiprazol also shows moderate affinity concerning serotoninovy receptors and has no noticeable affinity of rather muskarinovy receptors. interaction with other receptors, except subtypes of dopamine and serotonin, can explain some other clinical effects of an aripiprazol.

Pharmacokinetics. Absorption. Aripiprazol is well soaked up, and his C _max in blood plasma is reached in 3–5 h after introduction. Aripiprazol is exposed to the minimum presistemny metabolism. The bioavailability of medicament at oral administration is 87%. Meal with the high content of fats does not influence pharmacokinetics of an aripiprazol.

Distribution. Aripiprazol is widely distributed in body tissues. The volume of distribution is 4.9 l/kg that indicates big extravascular distribution. At introduction in therapeutic doses aripiprazol and degidroaripiprazol for more than 99% contact proteins of blood plasma, mainly albumine.

Biotransformation. Aripiprazol is substantially metabolized in a liver, generally by dehydrogenation, hydroxylation and N-dealkylation. According to data of the researches in vitro CYP enzymes 3A4 and CYP 2D6 are responsible for dehydrogenation and hydroxylation of an aripiprazol, and N-dealkylation is catalyzed by CYP 3A4. Aripiprazol is the main substance of the medicine which is in a system blood-groove. In an equilibrium state degidroaripiprazol — its active metabolite — makes about 40% of AUC of an aripiprazol in blood plasma.

Removal. T _½ aripiprazola makes about 75 h at persons with active metabolism of CYP 2D6 and about 146 h — at persons with slow metabolism are CYP 2D6.

General clearance of an aripiprazol is 0.7 ml/min., generally it is provided by hepatic clearance. After single dose inside of ¹⁴ C-mechennogo of an aripiprazol about 27% was removed with urine and about 60% — with a stake. Less than 1% of an aripiprazol in not changed look were removed with urine, about 18% of not changed aripiprazol — with a stake.

Pharmacokinetics in special groups of patients. Children. Patients at the age of 10–17 years had a similar pharmacokinetics of an aripiprazol and degidroaripiprazol that at adults after correction with a difference in body weight.

Patients of advanced age. Differences between pharmacokinetics of an aripiprazol at healthy volunteers of advanced age and younger patients are absent.

Floor. Differences between pharmacokinetics of an aripiprazol at healthy men and women are absent.

Smoking and race. Pharmacokinetic assessment of population did not reveal clinically significant, connected with race distinctions or influence of smoking on pharmacokinetics of an aripiprazol.

Renal failure. It is revealed that pharmacokinetic characteristics of an aripiprazol and degidroaripiprazol are identical as at patients with a serious illness of kidneys, and at young healthy volunteers.

Abnormal liver function. Patients have no sufficient data on metabolic features of an aripiprazol with abnormal liver functions.

Indication

for treatment of schizophrenia at adults.

also for treatment of moderate and heavy maniacal episodes in bipolar disorder of the I type and also for prevention of new maniacal episodes at the adults who earlier transferred maniacal episodes and responding to treatment aripiprazoly.

Use

Adult. schizophrenia: the recommended initial dose of medicament ariprazol makes 10 or 15 mg/days, and a maintenance dose — 15 mg/days accept this dose 1 time a day irrespective of meal.

in the range of doses of 10-30 mg/days. Increase in efficiency at reception of the doses exceeding a daily dose of 15 mg is not shown though the raised dose can be useful to certain patients.

Maximum daily dose should not exceed 30 mg.

Maniacal episodes in bipolar disorder of the I type: the recommended initial dose of the medicament Ariprazol makes 15 mg. This dose is accepted 1 time a day irrespective of meal. It is possible to appoint medicament as monotherapy or as a part of the combined treatment. For some patients there can be effective an increase in a dose. The maximum daily dose should not exceed 30 mg.

Prevention of new maniacal episodes in bipolar disorder of the I type: for prevention of a recurrence of maniacal episodes at the patients accepting aripiprazol in the form of monotherapy or as a part of the combined treatment it is necessary to continue administration of medicament in the same dose. In view of a clinical condition of the patient the correction of a daily dose, including its decrease is possible.

Patients with an abnormal liver function: with weak or moderate degree of a liver failure of dose adjustment it is not required to patients. For providing recommendations to patients with heavy abnormal liver functions not enough the available data. These patients should select a dose carefully. At patients with a heavy abnormal liver function to apply the maximum daily dose of 30 mg with care.

Patients with a renal failure: with a renal failure of dose adjustment it is not required from patients.

Patients of advanced age: the efficiency of the medicament Ariprazol in treatment of schizophrenia and bipolar disorder of the I type for patients aged from 65 years is not established. In view of higher sensitivity of this population of patients, it is necessary to consider expediency of use of lower initial doses of medicament if other clinical factors allow.

Floor: dose adjustment depending on a sex of the patient is not required.

Smoking: taking into account a way of metabolism of an aripiprazol it is not required to smokers of dose adjustment.

Dose adjustment as a result of interactions: in case of simultaneous administration of powerful CYP inhibitors 3A4 or CYP 2D6 with aripiprazoly the dose of an aripiprazol should be lowered. If CYP inhibitor 3A4 or CYP 2D6 is excluded from the scheme of the combined treatment, the dose of an aripiprazol should be raised.

in case of simultaneous introduction of powerful inductors CYP 3A4 with aripiprazoly a dose of an aripiprazol should be raised. If inductor CYP 3A4 is excluded from the scheme of the combined treatment, the dose of an aripiprazol should be lowered till recommended.

Contraindication

Hypersensitivity to an aripiprazol or any other component of drug.

Side effects

Most frequent undesirable reactions were an akathisia and nausea.

by such conditional parameters: often (≥1/100–1/10) and infrequently (≥1/1000–1/100):

from mentality: often — excitement, insomnia, concern; infrequently — a depression, hyper sexuality.

from nervous system: often — extrapyramidal disturbances, an akathisia, a tremor, dizziness, drowsiness, sedation, a headache.

from an organ of sight: often — blurring of sight; infrequently — a diplopia.

from a cardiovascular system: infrequently — tachycardia, orthostatic hypotension.

from digestive system: often — dyspepsia, nausea, vomiting, a constipation, excessive salivation.

General disorders: often — fatigue.

Frequency of the following reactions is considered the unknown (it cannot be estimated on the available data):

from an endocrine system: giperprolaktinemiya.

from blood and lymphatic system: leukopenia, neutropenia, thrombocytopenia.

from the immune system: allergic reactions (for example anaphylactic reactions, Quincke's disease, paraglossa, face edema, itching, small tortoiseshell).

from an endocrine system: hyperglycemia, diabetes, diabetic ketoacidosis, diabetic giperosmolyarny coma.

from a metabolism: increase or degrowth of a body, anorexia, hyponatremia.

from mentality: excitement, nervousness, pathological passion for gamblings, aggression, attempts of a suicide, suicide thinking and complete suicide.

from nervous system: disturbance of the speech, malignant antipsychotic syndrome (MAS), big convulsive attack, serotoninovy syndrome.

from heart: lengthening of an interval Q–T, ventricular arrhythmia, sudden death, a stop of warm activity, ventricular tachycardia on type a pirouette, bradycardia.

from vessels: faints, AG, venous thrombembolia (VTE; including a pulmonary embolism and a deep vein thrombosis).

from the respiratory system, bodies of a thorax and mediastinum: oropharyngeal spasm, laryngospasm, aspiration pneumonia.

from digestive system: pancreatitis, a dysphagy, discomfort in a GIT, diarrhea.

from a liver and biliary tract: liver failure, jaundice, hepatitis, increase in the AlAT, AsAT level, gamma glutamiltransferazy, SF.

from skin and hypodermic fabrics: rash, a photosensitization, an alopecia, the increased sweating.

from musculoskeletal and connective tissue: rhabdomyolysis, myalgia, muscle tension.

Pregnancy, postnatal and perinatal states: a medicament withdrawal at newborns.

from kidneys and urinary tract: urine incontinence, urination delay.

from genitals and a mammary gland: priapism.

Complication of the general character and reaction in the injection site: disturbance of temperature regulation (for example hypothermia, hyperthermia), stethalgia, peripheral hypostasis.

Laboratory researches: increase in the KFK level, increase in level of glucose in blood, fluctuations of level of glucose in blood, increase in level of glikozilirovanny hemoglobin.

with

At treatment from several days to several weeks. during this period it is necessary to conduct careful observation of a condition of patients.

Tendency to a suicide: emergence of suicide behavior is inherent in patients with psychotic diseases and affective disorders. In certain cases it was noted soon after the beginning of use of neuroleptics or transition from one neuroleptic to another, including treatment aripiprazoly. Treatment by neuroleptics has to be followed by careful observation of the patients belonging to group of the increased risk.

Knows that there is no increased risk of emergence of suicide tendency at use of an aripiprazol in comparison with use of other neuroleptics.

Cardiovascular disorders: aripiprazol it is necessary to apply with care at patients in whose anamnesis there are cardiovascular diseases (myocardial infarction or an ischemic heart disease, heart failure or disturbance of conductivity), the cerebrovascular disturbances, states causing tendency of patients to arterial hypotension (dehydration, a hypovolemia, use of antihypertensive medicines) or AG including the progressing or malignant AG.

by

At treatment by neuroleptics registered VTE cases. As at the patients accepting neuroleptics the acquired risk factors of VTE are often noted, to and during treatment aripiprazoly all possible risk factors of emergence of VTE have to be revealed and all preventive measures are taken.

Lengthening of an interval of Q-T: as well as other neuroleptics, aripiprazol it is necessary to apply with care at patients in whose family anamnesis there are cases of lengthening of an interval of Q-T.

Late dyskinesia: in case of symptoms of late dyskinesia in the patient accepting aripiprazol it is necessary to consider expediency of a dose decline of medicament or the termination of treatment. The specified symptoms can temporarily become aggravated or even to arise after the treatment termination.

Other extrapyramidal symptoms: at use of an aripiprazol for children there were an akathisia and parkinsonism. In case of signs of other extrapyramidal symptoms it is necessary to consider the possibility of a dose decline and a message careful clinical monitoring of a condition of the patient.

ZNS: ZNS represents a complex of the symptoms connected with use of medicinal means neuroleptics which can potentially have a lethal outcome.

Clinical manifestations of ZNS are the hyper pyrexia (extremely high temperature of a body), muscular rigidity, the changed mental status and symptoms of disorder from the autonomic nervous system (irregular pulse or the ABP, tachycardia, the strengthened sweating and cardiac arrhythmia). Accessory signs can include increase in the KFK level, a myoglobinuria (rhabdomyolysis) and OPN. However also the separate cases of increase in the KFK level and a rhabdomyolysis which are not necessarily connected with ZNS are noted. In case of emergence in the patient of symptoms of ZNS or inexplicable very high temperature of a body without additional clinical manifestations of ZNS intake of all antipsychotic medicines, including an aripiprazola, it is necessary to stop.

Epileptic seizures: exceptional cases of epileptic seizures at treatment are celebrated aripiprazoly. Therefore aripiprazol it is necessary to apply with care at patients with epilepsy in the anamnesis or existence of the states connected with epileptic seizures.

Patients of advanced age with psychosis against the background of dementia. The increased mortality: at use of an aripiprazol for patients of advanced age with psychosis against the background of Alzheimer's disease the risk of a lethal outcome is increased. Though the reasons of lethal outcomes were different, most of them had cardiovascular (for example heart failure, sudden death) or infectious (for example pneumonia) the nature.

Undesirable reactions of cerebrovascular character: at patients of advanced age with psychosis against the background of Alzheimer's disease undesirable reactions of cerebrovascular type (for example a stroke, the tranzitorny ischemic attack), including with a lethal outcome developed.

by

noted the significant interrelation between doses of medicament and emergence of undesirable reactions of cerebrovascular type in the patients accepting aripiprazol.

Aripiprazol is not shown to

for treatment of psychosis against the background of dementia.

Hyperglycemia and diabetes: the hyperglycemia, in certain cases very heavy and connected with ketoacidosis or a giperosmolyarny coma, including with a lethal outcome, is noted at the patients accepting atypical neuroleptics, in particular aripiprazol. Risk factors of heavy complications include obesity and presence of diabetes in the family anamnesis. There is no exact comparative risk assessment of development of the undesirable reactions connected with a hyperglycemia at the patients accepting aripiprazol and other atypical neuroleptics. It is necessary to watch carefully a condition of the patients accepting any neuroleptics including aripiprazol, fixing hyperglycemia symptoms (such as polydipsia, polyuria, polyphagia and weakness), and the condition of patients with diabetes or risk factors of developing diabetes needs to be controlled regularly concerning increase in level of glucose.

Hypersensitivity: as well as in case of use of other medicines, at reception of an aripiprazol, reactions of hypersensitivity can develop.

Increase in body weight. At patients with schizophrenia and a bipolar mania often note increase in body weight owing to associated diseases, uses of the neuroleptics causing, as we know, increase in body weight and also lack of a healthy lifestyle; this phenomenon can lead to serious complications. At treatment aripiprazoly cases of increase in body weight at patients with considerable risk factors, such as diabetes, disturbances, as a rule, are recorded from a thyroid gland or hypophysis adenoma in the anamnesis.

Aripiprazol does not cause clinically significant increase in body weight in adults.

Dysphagy: neuroleptics, including aripiprazol, can cause disturbances of motility of a gullet and aspiration of gastric contents. Aripiprazol and other neuroleptics it is necessary to apply with care at patients with the increased risk of aspiration pneumonia.

Pathological tendency to gamblings: at patients to whom it was appointed aripiprazol, cases of pathological tendency to gamblings are noted irrespective of whether they had a similar dependence in the past. Patients with pathological tendency to gamblings in the anamnesis can enter into group of the increased risk, it is necessary to watch their state carefully.

Lactose: the tablets Ariprazol contain lactose. To patients with rare inherited disorders, such as intolerance of a galactose, deficiency of Lappa lactase or disturbance of absorption of glucose galactose, it is not necessary to take this drug.

Patients with the accompanying syndrome of deficit of attention and hyperactivity: despite the high frequency of associated diseases of bipolar disorder of the I type and syndrome of deficit of attention and hyperactivity, data on safety of simultaneous use of an aripiprazol and stimulators are limited therefore at co-administration of these means the extreme care is necessary.

Use during pregnancy and feeding by a breast. Pregnancy. Adequate controlled researches of an aripiprazol with participation of pregnant women were not conducted. It was reported about congenital anomalies, however existence of relationship of cause and effect with reception of an aripiprazol it is not established. The known data of researches on animals do not allow to exclude a possibility of an embriofetotoksichnost. Patients should report to the doctor about approach of pregnancy or intention to become pregnant during treatment aripiprazoly. In connection with insufficient information about safety of use of an aripiprazol during pregnancy it is only possible to appoint it when the expected advantage for the pregnant woman exceeds potential risk for a fruit.

At newborns whose mothers accepted neuroleptics (including aripiprazol) in the III trimester of pregnancy, undesirable reactions, including extrapyramidal symptoms and/or a withdrawal which can be various on weight and duration are possible

. It is known of cases of excitement, increase or decrease in a muscle tone, a tremor, drowsiness, disturbances of breath or problems with feeding. Therefore, it is necessary to watch a condition of such newborns carefully.

Breastfeeding. Aripiprazol is allocated with breast milk. In case of need administration of medicament feeding by a breast should be stopped.

Children. The medicament Ariprazol in this dosage is not recommended to use for children.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Aripiprazol, as well as other neuroleptics, can affect ability to run vehicles owing to side reactions from nervous system and an organ of sight (see. Side EFFECTS). In the course of treatment it is recommended to refrain from control of motor transport or work with other mechanisms, will not become known sensitivity of patients to medicament yet.

Owing to antagonism to α1-адренорецепторам aripiprazol the effect of some antihypertensive medicaments can strengthen

Interaction.

Considering the main influence of an aripiprazol on central nervous system, it is necessary to be careful when assigning an aripiprazol with other medicines influencing central nervous system in connection with possible cross undesirable reactions, such as sedative action.

needs Also to refuse alcohol intake during therapy aripiprazoly. It is necessary to apply with care aripiprazol in combination with other medicines extending an interval of Q-T or breaking electrolytic balance.

Potential influence of other medicines on action of an aripiprazol

Inhibitor of secretion of hydrochloric acid, the antagonist of H ₂ - receptors famotidine reduces the speed of absorption of an aripiprazol, but this effect is not considered clinically significant.

Aripiprazol is metabolized by

in several ways with participation of CYP enzymes 2D6 and CYP 3A4, but not CYP enzymes 1A. Thus, it is not required to smokers of dose adjustment.

Quinidine and other CYP inhibitors 2D6. The dose of an aripiprazol needs to be lowered approximately half in case of its concomitant use with quinidine. Other powerful CYP inhibitors 2D6, such as fluoxetine and paroksetin probably make similar impact therefore the dose decline in case of their use has to be the same.

Ketokonazol and other CYP inhibitors 3A4. Persons with slow metabolism have CYP 2D6 the concomitant use of powerful CYP inhibitors 3A4 can lead to emergence of higher concentrations of an aripiprazol in blood plasma in comparison with patients with active metabolism of CYP 2D6. In case of need simultaneous use of a ketokonazol or other powerful CYP inhibitors 3A4 with aripiprazoly the potential benefits have to exceed possible risks for the patient. At simultaneous use of an aripiprazol and ketokonazol the dose of an aripiprazol is required to be lowered approximately half. Other powerful CYP inhibitors 3A4, such as itrakonazol and HIV protease inhibitors, theoretically can have the same effects, therefore, it is necessary to reduce doses similarly.

After the termination of intake of CYP inhibitor 2D6 or CYP 3A4 a dose of an aripiprazol needs to be raised to applied prior to the beginning of the accompanying treatment.

Perhaps slight increase of concentration of an aripiprazol in case of simultaneous use of weak CYP inhibitors 3A4 (for example diltiazem or an estsitalopram) or CYP 2D6.

Carbamazepine and other CYP inhibitors 3A4. The dose of an aripiprazol needs to be doubled in case of its concomitant use with carbamazepine. Other powerful inductors CYP 3A4 (for example rifampicin, rifabutin, Phenytoinum, phenobarbital, Primidonum, efavirenz, not Virapinum and a St. John's wort which is made a hole) theoretically have similar influence therefore the corresponding increase in a dose is necessary. After the termination of reception of powerful inductors CYP 3A4 the dose of an aripiprazol should be lowered till recommended.

Valproatum and lithium. In case of a concomitant use of Valproatum or lithium with aripiprazoly clinically significant changes of concentration of an aripiprazol are noted.

Serotoninovy syndrome. At the patients accepting aripiprazol cases of a serotoninovy syndrome are registered; especially at simultaneous use with other serotonergic drugs, such as selection inhibitor of the return capture of serotonin / selection inhibitor of the return capture of serotonin/noradrenaline, or with the medicaments increasing concentration of an aripiprazol.

Potential influence of an aripiprazol on effect of other medicines

Is improbable

that aripiprazol it is capable to cause clinically important medicinal interactions mediated by CYP enzymes 2D6 (a ratio dextromethorphan / 3-метоксиморфин), CYP 2C9 (warfarin), CYP 2C19 (omeprazolum) and CYP 3A4 (dextromethorphan).

by

in case of a concomitant use of an aripiprazol with Valproatums, lithium or lamotridzhiny noted clinically significant changes of concentration of Valproatum, lithium or lamotrigin.

Overdose

At patients described cases of intentional or accidental acute overdose of an aripiprazol by doses up to 1260 mg without a further lethal outcome. the lethargy, increase hell, drowsiness, tachycardia, nausea, vomiting and diarrhea were noted symptoms, potentially important from the medical point of view.

besides, obtained data on the accidental overdose only an aripiprazola (in a dose up to 195 mg) at children which did not have a lethal outcome. Drowsiness, a short-term loss of consciousness and extrapyramidal symptoms were noted symptoms, potentially important from the medical point of view.

Treatment of overdose has to include maintenance therapy, ensuring passability of airways, oxygenotherapy, IVL and also control of symptoms. It is necessary to take a possibility of overdose of numerous medicines into account. Therefore it is necessary to begin immediately control of a condition of a cardiovascular system which has to include continuous monitoring of the ECG for detection of possible arrhythmias.

After the confirmed or probable overdose of an aripiprazol needs careful medical observation and control of a condition of the patient before his restoration.

Activated carbon (50 g) applied in 1 h after reception of an aripiprazol reduced an indicator of the C _max an aripiprazola approximately for 41%, and AUC indicator — approximately for 51% that indicates possible efficiency of activated carbon in overdose treatment.

Though information on influence of a hemodialysis for treatment of overdose of an aripiprazol is absent, it is improbable that the hemodialysis could be useful in overdose treatment as aripiprazol substantially contacts proteins of blood plasma.

Storage conditions

In original packing at a temperature not above 25 °C.