Universal reference book for medicines
Product name: ZILAKSERA ® (ZYLAXERA ® )

Active substance: aripiprazole

Type: Antipsychotic drug (antipsychotic)

Manufacturer: КРКА-РУС (Russia)
Composition, form of production and packaging
Tablets are
capsular, slightly biconcave, light pink with marbling and dark impregnations.

1 tab.

aripiprazole fumarate semi-finished granule 148.5 mg,

in t.ch.
aripiprazole fumarate 11.3 mg,
which corresponds to aripiprazole 10 mg


1 tab.

aripiprazole fumarate semi-finished granule 11.3 mg,

which corresponds to the content of aripiprazole 10 mg

Auxiliary substances of semifinished products-granules: lactose monohydrate - 98.95 mg, corn starch - 17.36 mg, microcrystalline cellulose - 17.36 mg, giprolase - 3.46 mg, ferric oxide red oxide (E172) - 0.07 mg.

Excipients: magnesium stearate - 1.5 mg.

14 pcs.
- packings cellular planimetric (2) - packs cardboard.
Tablets are round, slightly biconcave, with a facet, light yellow with marbling and possible dark impregnations.

1 tab.

aripiprazole fumarate semi-finished granule 222.75 mg,

in t.ch.
aripiprazole fumarate 16.95 mg,
which corresponds to aripiprazole 15 mg

Auxiliary substances of semifinished products-granules: lactose monohydrate - 148.42 mg, corn starch - 26.04 mg, microcrystalline cellulose - 26.04 mg, giprolase - 5.19 mg, ferric oxide yellow oxide (E172) - 0.11 mg.

Excipients: magnesium stearate - 2.25 mg.

14 pcs.
- packings cellular planimetric (2) - packs cardboard.
Tablets are round, slightly biconcave, with a facet, light pink color with marbling and dark impregnations.

1 tab.

aripiprazole fumarate semifinished-granules 445.5 mg,

in t.ch.
aripiprazole fumarate 33.9 mg,
which corresponds to aripiprazole 30 mg

Auxiliary substances of semifinished products-granules: lactose monohydrate - 296.84 mg, corn starch - 52.08 mg, microcrystalline cellulose - 52.08 mg, giprolose - 10.38 mg, ferric oxide red oxide (E172) - 0.22 mg.

Excipients: magnesium stearate - 4.5 mg.

14 pcs.
- packings cellular planimetric (2) - packs cardboard.
Tablets are capsular, slightly biconvex, light-blue with marbling and possible dark impregnations.

1 tab.

aripiprazole fumarate semi-finished granule 5.65 mg,

which corresponds to the content of aripiprazole 5 mg

Auxiliary substances of semifinished products-granules: lactose monohydrate - 49.47 mg, corn starch - 8.67 mg, microcrystalline cellulose - 8.67 mg, giprolose - 1.73 mg, dye blue (dye blue patented (E131), dye diamond black (E151)) - 0.06 mg.

Excipients: magnesium stearate - 0.75 mg.

14 pcs.
- packings cellular planimetric (2) - packs cardboard.
14 pcs.
- packings cellular planimetric (4) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2010.

PHARMACHOLOGIC EFFECT

It is assumed that the therapeutic effect of aripiprazole in schizophrenia is due to a combination of partial agonistic activity against D2-dopamine and 5HT1a-serotonin receptors and antagonistic activity against 5HT2a-serotonin receptors.

Aripiprazole has a high affinity in vitro to D2 and D3-dopamine receptors, 5HT1a and 5HT2a-serotonin receptors and moderate affinity for D1-dopamine, 5HT2- and 5HT7-serotonin,?
1- adrenoreceptors and histamine H 1 -receptors.
Aripiprazole is also characterized by moderate affinity for the sites of serotonin reuptake and lack of affinity for muscarinic cholinergic receptors.
Aripiprazole in animal experiments exhibited antagonism with respect to dopaminergic hyperactivity and agonism with respect to dopaminergic hypoactivity. Some clinical effects of aripiprazole can be explained by interaction with other receptors, in addition to dopamine and serotonin.
PHARMACOKINETICS

The mean T 1/2 of aripiprazole is about 75 hours. C ss is reached after 14 days.
Cumulation of the drug with multiple admission is predictable. The pharmacokinetics of aripiprazole in equilibrium
are proportional to the dose.
There were no daily fluctuations in the distribution of aripiprazole and its metabolite dehydroaripiprazole. It was found that the main metabolite of the drug in human plasma, dehydroaripiprazole, has the same affinity for D2-dopamine receptors as aripiprazole.
Aripiprazole is rapidly absorbed after ingestion, while C max aripiprazole in plasma is reached after 3-5 hours.

Bioavailability of the preparation Zilaxera at oral intake is 87%.
Eating food does not affect the bioavailability of aripiprazole.
Aripiprazole is well distributed in tissues, with an apparent V d of 4.9 l / kg, indicating an intensive extravascular distribution.
At a therapeutic concentration of more than 99%, aripiprazole binds to blood serum proteins, mainly with albumin.
Aripiprazole does not affect the pharmacokinetics and pharmacodynamics of warfarin, that is, does not displace warfarin from its association with blood proteins.

Aripiprazole undergoes pre-systemic metabolism only to a minimal extent.
Aripiprazole is metabolized in the liver in three ways: dehydrogenation, hydroxylation and N-dealkylation. According to in vitro data, dehydrogenation and hydroxylation of aripiprazole occurs under the action of isoenzymes CYP3A4 and CYP2D6, and N-dealkylation is catalyzed by the CYP3A4 isoenzyme.
At equilibrium, the AUC of dehydroaripiprazole is approximately 40% of the aripiprazole AUC in the blood plasma.

After a single administration of 14 C-aripiprazole labeled, approximately 27% and 60% of radioactivity is determined in urine and feces, respectively.
Less than 1% of unchanged aripiprazole is determined in urine and approximately 18% of the dose taken is unchanged through the intestines with bile. The total clearance of aripiprazole is 0.7 ml / min / kg, mainly due to excretion by the liver.
INDICATIONS

- schizophrenia: acute attacks and maintenance therapy;

- Type 1 bipolar disorder: manic episodes and maintenance therapy to prevent relapse in patients with type I bipolar disorder who have recently undergone a manic or mixed episode.

DOSING MODE

Inside, 1 time / day, regardless of food intake.

Schizophrenia

The initial dose of 10-15 mg 1 time / day.
The maintenance dose is 15 mg / day.
In clinical trials, the effectiveness of the drug in doses of 10 to 30 mg / day is shown.

The maximum daily dose is 30 mg / day.

Manic episodes with bipolar disorder

The initial dose is 15-30 mg / day.

If necessary, dose adjustment is performed at intervals of at least 24 hours. In clinical trials, the efficacy of the drug at doses of 15-30 mg / day for manic episodes during admission for 3-12 weeks was demonstrated.
Safety of a dose above 30 mg / day in clinical studies was not evaluated. In the observation of patients with bipolar disorder type 1 who had a manic or mixed episode who had a symptom stabilization against aripiprazole (15 mg / day or 30 mg / day) for 6 months and further, for 17 months, a favorable the effect of such maintenance therapy. Periodically, patients should be examined to determine whether to continue supporting therapy.
Renal failure and liver failure (class A and B according to the Child-Pugh classification) - dose adjustment is not required.
Severe hepatic insufficiency (class C according to Child-Pugh classification) - it is recommended to carefully select the dose of the drug and with caution apply the maximum daily dose of 30 mg.
The experience of using the drug in patients older than 65 years is limited.
Given the high susceptibility of this population of patients and in the presence of alarming clinical factors, treatment with smaller doses should be started.
SIDE EFFECT

Classification of the incidence of side effects: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1/100), rarely (> 1/10 000 to <1/1000), very rarely (from <1/10000, including individual messages).

From the cardiovascular system: often - orthostatic hypotension, tachycardia;
infrequent - bradycardia, palpitations, myocardial infarction, QT interval prolongation, cardiac arrest, hemorrhages, atrial fibrillation, heart failure, AV blockade, myocardial ischemia, deep vein thrombosis, phlebitis, extrasystole, decreased blood pressure; rarely - vasovagal syndrome, enlargement of the heart, atrial flutter, thrombophlebitis, intracranial bleeding, cerebral ischemia; very rarely - faint.
From the side of the digestive system: very often - nausea, anorexia;
often - dry nasal mucosa, dyspepsia, a feeling of heaviness in the abdomen, vomiting, constipation; infrequent - increased appetite, gastroenteritis, difficulty swallowing, flatulence, gastritis, dental caries, gingivitis, hemorrhoids, gastroesophageal reflux, gastrointestinal hemorrhage, periodontal abscess, swelling of the tongue, stool incontinence, colitis, rectal hemorrhage, stomatitis, ulceration of the mucosa oral cavity, cholecystitis, fecaloma, mucous candidiasis of the oral cavity, cholelithiasis, belching, stomach ulcer; rarely - esophagitis, gum bleeding, glossitis, melena, intestinal bleeding, ulcer of duodenum, cheilitis, hepatitis, enlargement of liver, pancreatitis, perforation of the intestine, bloody vomiting; very rarely - increased activity of ALT and ACT, jaundice, dysphagia.
From the immune system: very rarely - allergic reactions: anaphylaxis, angioedema, laryngospasm, pruritus, urticaria.

From the musculoskeletal system: often - rigidity of muscles, myalgia, muscle cramps;
infrequently - ossalgia, arthralgia, myasthenia gravis, arthritis, arthrosis, muscle weakness, muscle spasms, bursitis; very rarely - increased activity of creatine phosphokinase (CK), rhabdomyolysis, tendonitis, tenobursitis, rheumatoid arthritis, myopathy;
From the nervous system: very often - insomnia, drowsiness, akathisia;
often - dizziness, tremor, extrapyramidal syndrome, psychomotor agitation, depression, nervousness, increased salivation, hostility, suicidal thoughts, mania, unsteady gait, confusion, resistance to performing passive movements (cogwheel syndrome), sedation; infrequent - dystonia, muscle twitching, decreased concentration, paresthesia, limb tremor, impotence, bradykinesia, decreased / increased libido, panic reactions, apathy, dyskinesia, memory loss, stupor, amnesia, stroke, hyperactivity, depersonalization, myoclonus, depressed mood, hyperreflexia, slowing of mental function, increased sensitivity to irritants, violation of oculomotor reaction; rarely - delirium, euphoria, bucco-glossal syndrome, akinesia, depression of consciousness down to loss of consciousness, hyporeflexia, obsessive thoughts, malignant neuroleptic syndrome; very rarely - speech disorder.
On the part of the respiratory system: often - shortness of breath, pneumonia;
infrequently - bronchospasm, epistaxis, hiccough, laryngitis; rarely hemoptysis, aspiration pneumonia, increased sputum production, dry mucous membrane of the nasal cavity, pulmonary edema, pulmonary embolism, hypoxia, respiratory insufficiency, apnea.
From the skin: often - dry skin, itching, excessive sweating, skin ulceration;
infrequently - acne, vesicle-bulbous rash, eczema, alopecia, psoriasis, seborrhea; rarely - maculopapular rash, exfoliative dermatitis, urticaria.
From the senses: often - conjunctivitis, pain in the ears;
infrequent - dry eyes, pain in the eyes, ringing in the ears, inflammation of the middle ear, cataracts, loss of taste, blepharitis; rarely - increased lacrimation, frequent flashing, external otitis media, amblyopia, deafness, diplopia, intraocular hemorrhage, photophobia.
From the genitourinary system: often - urinary incontinence;
infrequently - cystitis, frequent urination, leukorrhea, urinary retention, hematuria, dysuria, amenorrhea, premature ejaculation, vaginal bleeding, vaginal candidiasis, renal failure, uterine bleeding, menorrhagia, albuminuria, nocturia, polyuria, frequent urination; rarely - pain in the mammary gland, cervicitis, galactorrhea, anorgasmia, burning of the external genital organs, glucosuria, gynecomastia, nephrolithiasis, painful erection;very rarely - priapism.
From the side of metabolism: often - weight loss;
infrequently - dehydration, edema, hypercholesterolemia, hyperlipidemia hyperglycemia, hypokalemia, diabetes mellitus, thirst, increased blood urea, hyponatremia, iron deficiency anemia, hypercreatininemia, hyperbilirubinemia, increased lactate dehydrogenase (LDH) activity, obesity, increased alkaline phosphatase activity; rarely - hyperkalemia, gout, hypernatremia, cyanosis, urine acidification, hypoglycemia;
Other: often - flu-like syndrome, peripheral edema, pain in the chest, in the neck;
infrequent - swelling of the face, malaise, photosensitivity, pain in the jaw, chills, stiffness of the jaw, tension in the chest; rarely - sore throat, stiffness in the back, heaviness in the head, candidiasis, stiffness in the throat, Mendelssohn's syndrome, heat stroke.
CONTRAINDICATIONS

- hereditary galactosemia, lactase deficiency, glucose-galactose malabsorption;

- age under 18 years (effectiveness and safety not established);

- lactation period;

- hypersensitivity to aripiprazole or other components of the drug.

With caution : cardiovascular disease (ischemic heart disease or previous myocardial infarction, chronic heart failure or conduction disorders in the history);cerebrovascular diseases;
conditions predisposing to the development of arterial hypotension (dehydration, hypovolemia, hypotensive medication) due to the possibility of developing orthostatic hypotension or arterial hypertension, incl. progressing or malignant; hereditary conditioned syndrome of the extended QT interval on the ECG; epilepsy, convulsive seizures or diseases in which convulsions, diabetes mellitus, or the presence of risk factors for the development of diabetes mellitus (obesity, diabetes mellitus in a family history); patients with an increased risk of aspiration pneumonia because of the risk of developing a violation of the motor function of the esophagus and aspiration; patients of advanced age; severe hepatic impairment; patients with a high risk of suicide (psychotic diseases, bipolar disorders), in people aged 18-24 years due to the risk of suicidal behavior, pregnancy, the risk of hyperthermia (intense physical activity, overheating, anticholinergic drugs, dehydration).
PREGNANCY AND LACTATION

Adequate and well-controlled studies with aripiprazole in pregnant women have not been conducted.
It is recommended to inform the doctor about the onset of pregnancy or its planning. The drug Zilaxera can be taken during pregnancy if the potential benefit to the mother exceeds the potential risk to the fetus.
During treatment with Zilaxera, breastfeeding should be discontinued.

APPLICATION FOR FUNCTIONS OF THE LIVER

Renal failure - dose adjustment is not required.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Hepatic insufficiency (class A and B according to the Child-Pugh classification) - dose adjustment is not required.
Severe hepatic insufficiency (class C according to Child-Pugh classification) - it is recommended to carefully select the dose of the drug and with caution apply the maximum daily dose of 30 mg.
APPLICATION FOR CHILDREN

Contraindicated in children under the age of 18 years.

APPLICATION IN ELDERLY PATIENTS

With caution: patients of advanced age.

The experience of using the drug in patients older than 65 years is limited.
Given the high susceptibility of this population of patients and in the presence of alarming clinical factors, treatment with smaller doses should be started.
In patients with psychoses due to senile dementia, the risk of a lethal outcome increases with the treatment of atypical neuroleptics.
At psychoses in patients older than 65 years with Alzheimer's disease there were violations of the cardiovascular system: infarction, transient ischemic impairment of cerebral circulation, incl. with a lethal outcome. The use of aripiprazole in psychoses due to senile dementia and in elderly patients with Alzheimer's disease is not recommended.
SPECIAL INSTRUCTIONS

Suicide attempts - a tendency to suicidal thoughts and attempts is characteristic of psychoses, so drug therapy must be combined with careful medical supervision.
The drug Zilaxera should be prescribed in a minimum amount sufficient to treat the patient. In connection with the risk of suicidal thoughts and the development of suicidal behavior, the Zilaxer preparation should be used with extreme caution in persons aged 18-24 years. It is necessary to relate the risk of suicide and the benefits of using the drug.
Late dyskinesia - the risk of developing tardive dyskinesia increases with the duration of therapy with neuroleptics, so when you see Zilaxer's symptoms of late dyskinesia, you should reduce the dose of this drug or cancel it.
After the withdrawal of therapy, these symptoms may temporarily increase or even appear for the first time.
Malignant neuroleptic syndrome - in the treatment of neuroleptics, incl.
aripiprazole, a life-threatening symptom complex, known as malignant neuroleptic syndrome (CNS), is described. This syndrome is manifested by hyperpyrexia, muscle rigidity, mental disorders and instability of the autonomic nervous system (irregular heartbeats and BP, tachycardia, sweating and cardiac arrhythmias). In addition, sometimes there is an increase in activity of CK, myoglobinuria (rhabdomyolysis) and acute renal failure. In case of symptoms of NSA or unexplained fever, all antipsychotics, incl. drug Zilaxera, should be canceled.
Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases severe and accompanied by ketoacidosis, which can lead to hyperosmolar coma, or death, has been noted in patients treated with atypical antipsychotics. While the relationship between the reception of atypical neuroleptics and type hyperglycemic disorders remains unclear, patients diagnosed with diabetes must regularly determination of blood glucose concentration when taking atypical neuroleptics. Patients who present risk factors for diabetes
(obesity, diabetes mellitus family history) when receiving atypical neuroleptics should conduct determination of blood glucose concentration in the beginning of the course and periodically during ingestion. In all patients treated with atypical antipsychotics, requires constant monitoring of possible development of hyperglycemia symptoms including increased thirst, frequent urination, polyphagia, and weakness.
The risk of venous thromboembolism
The use of antipsychotic drugs, including Aripiprazole may be associated with the risk of venous thromboembolism. In this connection it should identify the risk factors for this complication before prescribing aripiprazole and during treatment with this drug. It may be necessary to take measures for the prevention of venous thromboembolism.
Psychosis associated with dementia and Alzheimer's
patients with psychosis caused by dementia, for the treatment of atypical antipsychotics increases mortality risk. In psychosis in patients over 65 years of age with Alzheimer's disease were observed violations of the cardiovascular system: heart attack, transient ischemic cerebrovascular accident, including fatal. The use of aripiprazole for psychosis caused by dementia in the elderly and patients with Alzheimer's disease is not recommended.
Impact on the ability to drive vehicles and manage mechanisms

In applying the drug Zilaksera as the use of other antipsychotics, patients should be warned about the dangers of working with complex technical devices and road management.
OVERDOSE

In clinical trials, instances of accidental or intentional overdose of aripiprazole are described with a single dose up to 1080 mg, not accompanied by death.
symptoms:depression of consciousness of varying severity, up to coma, nausea, vomiting, fatigue, diarrhea, drowsiness. In hospitalized patients found no clinically significant changes in vital signs, laboratory parameters and indicators on the electrocardiogram (ECG). Post-marketing experience in adult patients receiving a single 450 mg aripiprazole suggests the possible development tachycardia. Moreover, cases are described random aripiprazole in children (reception to 195 mg). Potentially dangerous symptoms of overdose include extrapyramidal, convulsive, dystonic, cardiovascular (prolongation of the QT interval on the ECG, atrial fibrillation) disorders and transient loss of consciousness.
Treatment:supportive care, ensuring adequate airway patency, oxygen therapy, an effective ventilation and symptomatic treatment. It will be appreciated drug reactions. Immediately should be started monitoring the performance of the heart with the registration of ECG to detect arrhythmias. After confirmed or suspected overdose of aripiprazole requires careful medical supervision until the disappearance of all symptoms.
Activated charcoal (50 g) inputted after 1 h after administration of aripiprazole reduced the AUC and C max aripiprazole 51 and 41%, respectively, which allows to recommend its use in overdose.
Although accurate data on the use of dialysis in overdose aripiprazole no beneficial effect of this method is unlikely, since aripiprazole hardly excreted by the kidneys in unchanged form and largely bound to plasma proteins.
DRUG INTERACTION

There were no significant effect blocker histamine H 2 receptor antagonists famotidine inducing potent inhibition of acid secretion in the stomach, the pharmacokinetics of aripiprazole.
Various metabolic pathway of aripiprazole, including with the participation of isoenzymes CYP2D6 and CYP3A4. In studies in healthy people potent inhibitors isoenzyme CYP2D6 (quinidine) and isozymes CYP3A4 (ketoconazole) aripiprazole reduced clearance when administered by 52% and 38%, respectively. Therefore it is necessary to reduce the dose of aripiprazole when used in combination with inhibitors of isozymes CYP3A4 and CYP2D6.
Receiving 30 mg aripiprazole together with carbamazepine, a potent inducer isoenzyme CYP3A4, accompanied by a decrease by 68% and 73% of C max and AUC aripiprazole, respectively, and decreased by 69% and 71% Cmax and AUC degidroaripiprazola its active metabolite, respectively. You can expect similar effects and other powerful inducers of isoenzymes CYP3A4 and CYP2D6.
The metabolism of aripiprazole in vitro do not participate isozymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1, in connection with which it is unlikely its interaction with drugs and other factors (e.g., smoking), able to induce or inhibit these enzymes.
Simultaneous treatment with lithium or valproate 30 mg aripiprazole had no clinically significant effect on the pharmacokinetics of aripiprazole.
In clinical studies, aripiprazole at doses of 10-30 mg / day to significantly affect the metabolism of CYP2D6 substrates (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin) and CYP3A4 (dextromethorphan). Furthermore, aripiprazole and its major metabolite degidroaripiprazol not alter metabolism involving isoenzyme CYP1A2 in vitro. It is unlikely clinically significant effect of aripiprazole on drugs metabolized with the participation of these enzymes.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug was stored at a temperature not higher than 30 ° C, in the original package.
Keep out of the reach of children. Shelf life - 2 years.
Do not use the drug after the expiration date.

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