Arip MT

General characteristics. Structure:

Active ingredient: 10 mg or 15 mgaripiprazol (in the form of granulate).

Excipients: mannitol (Е 421), ferrous oxide yellow (Е 172), silicon dioxide colloid anhydrous, magnesium stearate, aspartame (Е 951), fragrance pineapple, mango fragrance, кросповидон, talc, citric acid, monohydrate.

Pharmacological properties:

Pharmacodynamics. Therapeutic action of an aripiprazol at schizophrenia is caused by a combination of partial agonistic activity concerning D2 dopamine and 5HT1a serotoninovy receptors and antagonistic activity concerning 5HT2 of serotoninovy receptors.

Aripiprazol has high affinity of in vitro to D2 and D3 of dopamine receptors 5HT1a and 5HT2a serotoninovy receptors and moderate affinity to D4 dopamine, 5HT2c and 5HT7 of serotoninovy receptors, a1-adrenoceptors and H1-histamine receptors. Aripiprazol is characterized by also moderate affinity to sites of the return serotonin reuptake and lack of affinity to muskarinovy receptors. Aripiprazol in experiments on animals showed antagonism concerning a dofaminergichesky hyperactivity and an agonizm the relation dofaminergichesky гіпоактивності. Not only with dopamine and serotoninovy receptors the aripiprazol can explain with interaction some clinical effects.

Pharmacokinetics. Activity of drug Arip MT is caused by active ingredient – aripiprazoly. The average elimination half-life of an aripiprazol makes about 75 hours. Equilibrium concentration is reached in 14 days. Cumulation of drug at multiple dose is predictable. Pharmacokinetics indicators to an arip_prazol in an equilibrium state are proportional to a dose. Daily fluctuations of distribution an arip_prazola and its metabolite of a degidroaripiprazol are noted. It is established that the main metabolite of drug in plasma of the person, дегидроарипипразол, has the same affinity to D2 of dopamine receptors, as well as арипипразол.

Aripiprazol is quickly soaked up after administration of drug Arip by MT, at the same time the maximum concentration of drug in plasma is reached in 3 - 5 hours. Absolute bioavailability of tablets Arip makes MT 87%. Meal does not influence bioavailability of an aripiprazol.

At therapeutic concentration more than 99% of an aripiprazol contact proteins of serum, mainly albumine. Aripiprazol is exposed to presistemny metabolism only in the minimum degree. Aripiprazol is metabolized in a liver in three ways: dehydrogenation, to a hydroxylation and Ndezalkilirovaniyu. According to in vitro experiments, dehydrogenation and a hydroxylation of an aripiprazol happens under the influence of CYP3A4 and CYP2D6 enzymes, and Ndezalkilirovaniya is catalyzed by CYP3A4 enzyme. Aripiprazol is the main component of medicine in blood. At an equilibrium state the area under a curve "concentration time" (AUC) makes a degidroaripiprazola about 39% of AUC of an aripiprazol in plasma.

After a single dose a marked [14C] arip_prazola about 27% and 60% of radioactivity is defined in urine and Calais respectively. Less than 1% of an invariable aripiprazol are defined in urine and about 18% of the accepted dose in not changed look are removed with a stake. The general clearance of an aripiprazol makes 0,7 ml/min., mainly due to removal by a liver.

Indications to use:

Treatment of bad attacks of schizophrenia and for a maintenance therapy at patients with schizophrenia.

Treatment of acute maniacal episodes of bipolar disorder of the I type and for a maintenance therapy at patients with bipolar disorder of the I type who before it transferred the maniacal or mixed episode.

Route of administration and doses:

Schizophrenia. Arip is recommended to appoint MT in an initial dose of 10 or 15 mg once a day, irrespective of meal. The maintenance dose makes 15 mg a day. Efficiency of drug in doses from 10 to 30 mg a day is proved.

Maniacal episodes at bipolar disorder. Arip MT should accept 1 time a day irrespective of meal, since a dose of 15 or 30 mg a day. Change of a dose if necessary it is necessary to spend not less than 24 hours with an interval. In clinical trials efficiency of drug in doses of 15 - 30 mg/days at maniacal episodes at reception within 3 - 12 weeks is shown. Safety of doses higher than 30 mg a day was not estimated therefore it is not necessary to exceed a daily dose more than 30 mg.

At observation of patients with bipolar disorder of the I type and the maniacal or mixed episodes which had no symptoms at administration of drug Arip MT (15 mg or 30 mg/days at an initial dose of 30 mg a day) within 6 weeks, such maintenance therapy it is necessary to consider effective. It is necessary to inspect periodically patients for definition of need of continuation of a maintenance therapy.

His patients do not need change of a dosage of drug at appointment with a renal/liver failure (a class A, B and C on classification of Chaylda-Pyyu).

Though experience of use of drug by patients is aged more senior than 65 years is limited, correction of a dose for this category of patients is not required.

Features of use:

Use during pregnancy or feeding by a breast. Adequate and well controlled researches at pregnant women were not conducted. During pregnancy Arip MT can appoint only when the expected advantage for mother exceeds potential risk for a fruit. There is no sufficient experience of use of drug during feeding by a breast. In need of use of drug it is necessary to stop feeding by a breast.

Children. Do not apply to children.

Features of use. Suicidal attempts – tendency to suicide thoughts and to attempts is characteristic of psychoses therefore therapy needs to be combined with careful medical observation. It is necessary to appoint drug Arip MT in the minimum quantity sufficient for treatment of the patient; it will reduce risk of overdose.

Late dyskinesia – risk of development of late dyskinesia increases in process of increase in duration of therapy by neuroleptics therefore with the advent of symptoms of late dyskinesia at use Arip MT should reduce a dose of this drug or to cancel it. After therapy cancellation these symptoms can temporarily amplify or even for the first time to appear.

The malignant antipsychotic syndrome – at treatment by neuroleptics, including arip_prazoly, is described the life-threatening symptom complex known under the name "malignant antipsychotic syndrome" (ZNS). This syndrome is shown by a hyper pyrexia, muscular rigidity, disturbances of mentality and instability of the autonomic nervous system (irregular pulse and arterial pressure, tachycardia, perspiration and arrhythmias of heart). Besides, sometimes there are an increase in activity of a kreatinfosfokinaza, a myoglobinuria (рабдомиолиз) and an acute renal failure. In case of symptoms of ZNS or inexplicable fever all neuroleptics, including Arip of MT, it is necessary to cancel.

The hyperglycemia and diabetes mellitus hyperglycemia in certain cases expressed and connected with ketoacidosis which can lead to a giperosmolyarny coma and even a lethal outcome, was noted at the patients accepting atypical neuroleptics. Though communication between reception of atypical neuroleptics and disturbances of hyper glycemic type remains not clear, patients at whom the diabetes mellitus is revealed need to carry out regularly determination of level of glucose to blood at reception of atypical neuroleptics. Patients who have risk factors of emergence of a diabetes mellitus (obesity, existence of diabetes in a family at reception of atypical neuroleptics it is necessary to carry out determination of level of glucose to blood at the beginning of a course and periodically in the course of administration of drug. Any patients accepting atypical neuroleptics require constant observation of development of symptoms of a hyperglycemia, including the increased thirst, the speeded-up urination, a polyphagia, weakness).

With care – to patients with cardiovascular diseases (with coronary heart disease or the postponed myocardial infarction, with heart failure and disturbances of conductivity), the cerebrovascular diseases and states contributing to arterial hypotension (dehydration, hypovolemia and reception of hypotensive drugs) in connection with a possibility of development of orthostatic hypotension at patients with convulsive attacks or diseases at which spasms are possible; at patients with the increased risk of a hyperthermia, for example at intensive exercise stresses, overheating, reception of anticholinergic drugs, at dehydration because of ability of neuroleptics to break thermal control, at patients with the increased risk of aspiration pneumonia because of risk of disturbance of motor function of a gullet and aspiration at the patients having obesity and in the presence of diabetes in a family.

Ability to influence speed of response at control of motor transport or work with other mechanisms. During treatment it is necessary to abstain from control of motor transport or work with other potentially dangerous mechanisms.

Side effects:

From cardiovascular system: very seldom widespread – a syncope, seldom widespread – a vazovagalny syndrome, a cardiomegaly, an atrial flutter, thrombophlebitis, intracranial bleeding, the brain ischemia not widespread – bradycardia, a heart consciousness, a myocardial infarction, lengthening of QT of an interval, a cardiac standstill, hemorrhages, fibrillation of auricles, heart failure, an atrioventricular block, the myocardium ischemia, a deep vein thrombosis, phlebitis, premature ventricular contraction extended – orthostatic hypotension, tachycardia.

From a digestive tract: very seldom widespread – increase in activity of alaninaminotranspherase (ALT) and aspartate aminotransferase (nuclear heating plant) seldom widespread – an esophagitis, bleeding of gums, a language inflammation, vomiting with blood impurity, intestinal bleedings, the duodenum ulcer, a cheilitis, hepatitis, increase in a liver, pancreatitis, perforation of intestines not widespread – increase in appetite, a gastroenteritis, the complicated swallowing, a meteorism, gastritis, tooth caries, an ulitis, hemorrhoids, a gastroesophagal reflux, gastrointestinal hemorrhages, periodontal abscess, a paraglossa, an incontience a calla, colitis, rectal hemorrhages, stomatitis, ulcerations in a mouth, the cholecystitis, a fekaloma, candidiasis of a mucous membrane of a mouth, a zhelchekamenny disease, an eructation, stomach ulcer extended – the dyspepsia, vomiting, a lock very widespread – nausea, appetite loss.

From immune system: very seldom widespread – allergic reactions (an anaphylaxis, a Quincke's disease, an itch and a small tortoiseshell).

From a musculoskeletal system: very seldom widespread – increase in activity of a kreatinfosfokinaza, рабдомиолиз, the tendinitis, tendobursit, the pseudorheumatism, a myopathy not widespread – a joint pain and bones, a myasthenia, arthritis, arthrosis, muscular weakness, the spasms, a bursitis widespread – a mialgiya, spasms.

From a nervous system: seldom widespread – nonsense, euphoria, a bukkoglosalny syndrome, an akineziya, oppression of consciousness up to a loss of consciousness, the reduced reflexes, the notions of compulsion, a malignant antipsychotic syndrome not widespread – dystonia, twitchings of muscles, the easing of concentration of attention, paresthesia, a tremor of extremities, impotence, a bradykinesia which is lowered/increased by a libido, panic reactions, apathy, dyskinesia, memory easing, a stupor, amnesia, a stroke, a hyperactivity, depersonalization, a syndrome of uneasy legs (akathisia), a myoclonus, the suppressed mood, reinforced reflexes, delay of cogitative function, hypersensitivity to irritants, the hypotonia, disturbance of oculomotor reaction extended – dizziness, a tremor, an extrapyramidal syndrome, psychomotor excitement, a depression, nervousness, the increased salivation, hostility, suicide thoughts, maniacal thoughts, staggering gait, confusion of consciousness, resistance to performance of passive movements (cogwheel syndrome), are very widespread – sleeplessness, drowsiness, an akathisia.

From respiratory system: seldom widespread – a pneumorrhagia, aspiration pneumonia, the strengthened expectoration, a xeromycteria, a fluid lungs, an embolism of a pulmonary artery, a hypoxia, the respiratory insufficiency, an apnoea not widespread – bronchial asthma, nasal bleeding, a hiccups, laryngitis; frequent: short wind, pneumonia.

From skin: seldom widespread – makulopapulezny rash, exfoliative dermatitis, a small tortoiseshell; not widespread – the acne, vezikulobulezny (bubbly) rash, eczema, an alopecia (baldness), psoriasis, seborrhea extended – a xeroderma, an itch, the increased perspiration, skin ulcerations.

From sense bodys: seldom widespread – the strengthened dacryagogue, the frequent blinking, outside otitis, an amblyopia, deafness, a diplopia, eye hemorrhages, photophobia not widespread – dryness of an eye, eye pain, a ring in ears, an inflammation of a middle ear, a cataract, the taste loss, a blepharitis extended – conjunctivitis, ear pain.

From urinogenital system: seldom widespread – a mammary gland pain, a cervicitis, a galactorrhoea, an anorgazmiya, burning in the field of generative organs, a glycosuria, a gynecomastia (increase in mammary glands at men), the urolithiasis, a painful erection not widespread – cystitis, the speeded-up urination, bleach, an urination delay, a hamaturia, a dysuria, an amenorrhea, a premature ejaculation, vulval bleeding, vaginal candidiasis, a renal failure, uterine bleeding, a menorrhagia, an albuminuria, stones in kidneys, the nocturia, a polyuria, desires to an urination extended – an urine incontience.

Metabolic disturbances: seldom widespread – a hyperpotassemia, gout, a hypernatremia, cyanosis, the urine acidulation, hypoglycemic reaction not widespread – dehydration, hypostasis, a hypercholesterolemia, a hyperglycemia, a hypopotassemia, a diabetes mellitus, the increased ALT level, a lipidemia, a hypoglycemia, thirst, increase in content of urea in blood, a hyponatremia, the increased level of nuclear heating plant, increase in an alkaline phosphatase, an iron deficiency anemia, the raised creatinine, a bilirubinemia, the increased lactate dehydrogenase level, obesity widespread – loss of body weight, increase in level of a kreatinfosfokinaza.

Organism in general: seldom widespread – a pharyngalgia, constraint in spin, weight in the head, candidiasis, constraint in a throat, Mendelssohn's syndrome, heatstroke not widespread – pain in the field of a basin, a face edema, a febricula, a photosensitivity, a gnathalgia, a fever, constraint of jaws, abdominal distention, feeling of tension in the breasts extended – a grippopodobny syndrome, peripheral hypostasis, thorax pain, in a neck.

Interaction with other medicines:

Significant influence of H2 blocker of histamine receptors of famotidine is not revealed that causes considerable oppression of secretion of hydrochloric acid in a stomach, on pharmacokinetics to an arip_prazol.

Various ways of metabolism of an aripiprazol, including with participation of CYP2D6 and CYP3A4 enzymes are known. Healthy volunteers have powerful CYP2D6 inhibitors (quinidine) and CYP3A4 (кетоконазол) reduced clearance of an aripiprazol at reception by 52% and 38%, respectively. Therefore it is necessary to reduce a dose of an aripiprazol when using it in combination with CYP3A4 and CYP2D6 inhibitors.

Reception of 30 mg of an aripiprazol together with carbamazepine, the powerful inductor CYP3A4, was followed by decrease by 68% and 73% the maximum concentration in a blood plasma (Cmax) and the area under a curve "concentration time" (AUC) to an arip_prazol, respectively, and decrease by 69% and 71% of Cmax and AUC of its active metabolite of a degidroaripiprazol respectively. It is possible to expect similar action and other powerful inductors CYP3A4 and CYP2D6.

CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 enzymes in this connection its interaction with drugs and other factors (for example, smoking), capable _ng_b_ruvat is improbable do not participate in metabolism of an aripiprazol of in vitro or to activate these enzymes.

The concomitant use of lithium or Valproatum from 30 mg of an aripiprazol of QD did not exert clinically significant impact on pharmacokinetics of an aripiprazol.

Aripiprazol in doses of 10 - 30 mg a day on renders significant influence on metabolism of CYP2D6 substrates (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (омепразол, warfarin) and CYP3A4 (dextromethorphan). Besides, арипипразол and its main metabolite дегидроарипипразол did not change metabolism with participation of CYP1A2 in vitro enzyme. Clinically significant influence of an aripiprazol on drugs which are metabolized with the participation of these enzymes is improbable. Aripiprazol does not influence pharmacokinetics and a pharmacodynamics of warfarin, that is does not force out warfarin from communication with blood proteins.

Contraindications:

Hypersensitivity to an aripiprazol or to any other component which is a part of drug. Children's age.

Overdose:

Symptoms: nausea, vomiting, adynamy, diarrhea and drowsiness. At the hospitalized patients clinically significant changes of the main physiological indicators, laboratory parameters and an ECG are not revealed.

There were messages about accidental or intentional the overdoses of an aripiprazol with a single dose to 1080 mg which were not followed by a lethal outcome.

Post-marketing experience of a single dose by adult patients to 450 mg to an aripiprazol demonstrates possible development of tachycardia. Besides, overdose cases to an aripiprazol at children are described (reception to 195 mg). Extrapyramidal frustration and a loss of consciousness which quickly passes belong to potentially dangerous symptoms of overdose.

At overdose the maintenance therapy, ensuring adequate passability of respiratory tracts, oxygenation, effective ventilation of the lungs and a symptomatic treatment is required. It is necessary to consider medicinal reactions. Immediately it is necessary to begin monitoring of indicators of cardiac performance with registration of an ECG for detection of arrhythmias. After the confirmed or alleged overdose of an aripiprazol careful medical observation before disappearance of all symptoms is necessary.

Absorbent carbon (50 g), entered in 1 hour after reception of an aripiprazol, reduces the area under a curve "concentration time" and duration of stay and level of the maximum concentration in blood to an arip_prazol by 51% and 41% respectively that allows to recommend its use at overdose.

Though there are no reliable data about use of a hemodialysis at overdose of an aripiprazol, the favorable effect of this method is improbable because it арипипразол is not removed by kidneys in not changed look and substantially contacts proteins of plasma.

Storage conditions:

To store at a temperature not above 25 °C, in the place, dry, unavailable to children. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in a strip, on 3 strips in a cardboard pack.