Amdoal - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 63.077 mg, cellulose microcrystalline 10,000 mg, corn starch 6,983 mg, giprolose 3,800 mg, magnesium stearate 1,140 mg.

Tablets 15 mg:

Active substance: aripiprazole 15 mg;

Excipients: lactose monohydrate 94.615 mg, cellulose microcrystalline 15,000 mg, corn starch 10,475 mg, giprolose 5,700 mg, magnesium stearate 1,710 mg.

Tablets 20 mg:

Active substance: aripiprazole 20 mg;

Excipients: lactose monohydrate 126,153 mg, cellulose microcrystalline 20,000 mg, corn starch 13,967 mg, giprolose 7,600 mg, magnesium stearate 2,280 mg.

Tablets 30 mg:

Active substance: aripiprazole 30 mg;

Excipients: lactose monohydrate 189.230 mg, cellulose microcrystalline 30,000 mg, corn starch 20,950 mg, giprolose 11,400 mg, magnesium stearate 3,420 mg.

Description:Tablets white or almost white, round, biconvex, on one side is engraved: for the dosage of 10 mg "N74", 15 mg "N75", 20 mg "N76", 30 mg "N77".

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.X Other antipsychotics

N.05.A.X.12 Aripiprazole

Pharmacodynamics:

It is believed that the therapeutic effect of aripiprazole in schizophrenia is due to a combination of partial agonistic activity in relation to D2-dopamine and 5HT1a-serotonin receptors and antagonistic activity against 5HT2-serotonin receptors.

Aripiprazole has a high affinity in vitro to D2- and D3dopamine receptors, 5HT1a and 5HT2a-serotonin receptors and moderate affinity for D4-dopamine, 5HT2- and 5HT7-serotonin, a1-adrenoreceptors and H1-histamine receptors. Aripiprazole is also characterized by a moderate affinity for the sites of serotonin reuptake and the lack of affinity for muscarinic receptors. In animal experiments aripiprazole exhibited antagonism with respect to dopaminergic hyperactivity and agonism with respect to dopaminergic hypoactivity. Interaction not only with dopamine and serotonin receptors explains some clinical effects of aripiprazole.

Pharmacokinetics:

Suction

Aripiprazole is rapidly absorbed after oral administration. Eating food does not affect the bioavailability of aripiprazole. Absolute bioavailability with oral administration is 87%. The maximum concentration of aripiprazole in plasma (Cmah) is achieved in 3-5 hours. The equilibrium concentration (Css) is achieved after 14 days.

Distribution

Aripiprazole is intensively distributed in tissues, the apparent volume of distribution is 4.9 l / kg. The pharmacokinetics of aripiprazole in the equilibrium state are proportional to the dose. At a therapeutic concentration of more than 99%, aripiprazole binds to plasma proteins, mainly with albumin. The main metabolite of aripiprazole, dehydroaripiprazole, has the same affinity for D2dopamine receptors, as well as aripiprazole. There were no daily fluctuations in the distribution of aripiprazole and its metabolite dehydroaripiprazole.Area under the curve "concentration - time" (AUC) in the equilibrium state of dehydroaripiprazole is 39% of AUC aripiprazole in blood plasma.

Metabolism

Slightly subjected to pre-systemic metabolism. Aripiprazole is the main component of the drug in blood plasma. Aripiprazole metabolized in the liver by dehydrogenation, hydroxylation and N-dealkylation. In vitro dehydrogenation and hydroxylation of aripiprazole occurs with the participation of isoenzymes CYP3A4 and CYP2D6, a N-dealkylation - involving isoenzyme CYP3A4.

Excretion

The average half-life (T1 / 2) is approximately 75 hours for fast isoenzyme metabolizers CYP2D6 and about 146 hours for slow metabolizers. The total clearance of aripiprazole is 0.7 ml / min / kg, mainly due to excretion by the liver. After a single dose of the labeled ¹⁴With aripiprazole, approximately 27% of the dose was excreted by the kidneys and approximately 60% through the intestine. Less than 1% of unchanged aripiprazole is determined in urine and approximately 18% % The accepted dose in the unchanged form is deduced through an intestine.

Pharmacokinetics in specific patient groups

Children: taking into account the correction for body weight, the pharmacokinetics of aripiprazole and dehydroaripiprazole in adolescents 13-17 years corresponded to that of adults.

Elderly: There were no differences in the pharmacokinetics of aripiprazole in elderly and adult healthy volunteers. Also, the effect of age on pharmacokinetics in patients with schizophrenia has not been revealed.

Floor: There are no differences in pharmacokinetics in healthy men and women. Also, there was no evidence of gender influence on the pharmacokinetics of aripiprazole in patients with schizophrenia.

Smoking and race: In studies, there was no clinically significant effect of racial differences or the effect of smoking on the pharmacokinetics of aripiprazole.

Kidney diseases: The same pharmacokinetic parameters of aripiprazole and dihydroaripiprazole were revealed in patients with severe kidney disease and in young healthy volunteers.

Liver diseases: In patients with liver cirrhosis of various degrees (Child-Pugh classes A, B and C), after a single administration of aripiprazole, there was no significant effect of liver dysfunction on the pharmacokinetics of aripiprazole and dihydroaripiprazole. Due to the lack of data in patients with decompensated liver cirrhosis (Child-Pugh class C), it is impossible to draw definitive conclusions about metabolic activity.

Indications:

- Treatment of schizophrenia in adults;

- Treatment of manic episodes within the framework of bipolar I disorder and prevention of manic episodes in patients who had a history of manic episodes and had a clinical response to treatment with aripiprazole.

Contraindications:

- Hypersensitivity to one of the components of the drug;

- Age to 18 years;

- Lactation period;

- Senile dementia;

- Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Carefully:

Diseases of the cardiovascular system (coronary heart disease, including myocardial infarction, chronic heart failure, conduction disorders, conditions predisposing to lowering blood pressure (dehydration, hypovolemia, taking antihypertensive medications) due to the possibility of developing orthostatic hypotension; cerebrovascular diseases; epilepsy, diseases in which convulsions may develop, in patients at risk of developing aspiration pneumonia due to the risk of impairment the motor function of the esophagus and aspiration, in patients with an increased risk of hyperthermia, for example, with intense physical exertion, overheating, taking funds with m-cholinoblocking activity, dehydration due to the ability neuroleptics to disrupt thermoregulation; in patients with obesity; history of diabetes mellitus; pregnancy.

Pregnancy and lactation:

Adequate and well-controlled studies in pregnant women have not been conducted. Due to the lack of safety data, the drug can be taken during pregnancy only if the potential benefit to the mother exceeds the potential risk to the fetus. Patients should be warned about the need to immediately inform the doctor about the onset of pregnancy against the background of treatment with aripiprazole, and about the need to report on the planned pregnancy. In newborns whose mothers took neuroleptics during the third trimester of pregnancy, there is a risk of developing extrapyramidal disorders and / or withdrawal syndrome in the postpartum period. In newborns, excitation, increased or decreased blood pressure, tremor, drowsiness, respiratory distress syndrome, and feeding disorders were noted. Such newborns need careful observation.

During the treatment with aripiprazole, it is recommended to cancel breastfeeding. In studies on animals, data were obtained on the isolation of the drug with milk.There are no data on the penetration of aripiprazole into breast milk.

Dosing and Administration:

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

- Schizophrenia: the recommended initial dose of 10-15 mg once a day. The maintenance dose is usually 15 mg per day. The drug is effective at doses of 10 to 30 mg / day. An increase in the efficacy of doses above 15 mg / day has not been proven, but it may be necessary for some patients. The maximum daily dose should not exceed 30 mg.

- Manic episodes in bipolar disorder: the initial dose of 15 mg / day as a monotherapy or in combination. Some patients may require a higher dose. The maximum daily dose should not exceed 30 mg.

- Prevention of manic episodes with type I bipolar disorder: for the prevention of manic episodes in patients who had previously taken aripiprazole as monotherapy or in combination, continue treatment at the previous dose. Correction of the daily dose, including its reduction, is performed in accordance with state of the patient.

Application in special patents groups:

Patients with renal insufficiency.

Dose adjustments for prescribing patients with renal insufficiency are not required.

Patients with hepatic insufficiency.

Dose adjustments for prescribing patients with renal insufficiency are not required. However, patients with severe hepatic insufficiency should be cautious to prescribe a daily dose of 30 mg.

Use in patients over 65 years of age

Correction of the dose is not required.

The effect of sex on the dosing regimen

Dosage regimen for patients of both sexes is the same.

Dosage with concomitant therapy

With the simultaneous use of the drug Amdoal® and potent inhibitors of isoenzymes CYP2D6 or CYP3A4 the dose of Amdoal® should be halved. When cancellation of isozyme inhibitors CYP2D6 or CYP3A4, the dose of Amdoal® should be increased. Amdoal® should be used without changing dosing if it is prescribed as adjunctive therapy in patients with major depressive disorder. With the simultaneous use of Amdoal® and isoenzyme inducers CYP3A4 the dose of Amdoal® should be doubled. An additional dose increase of Amdoal® should be made taking into account clinical indications. When cancellation of isoenzyme inducers CYP3A4 the dose of Amdoal® should be reduced.With the appointment of several drugs that inhibit isoenzymes CYP2D6 and CYP3A4, should consider the possibility of reducing the daily dose of Amdoal®.

Side effects:

The most frequently reported side effects in placebo-controlled studies were akathisia and nausea, each of which occurred in more than 3% of patients who received aripiprazole orally.

The side effects listed below were more frequent (> 1/100) than in the placebo group, or were identified as adverse reactions possibly associated with the drug (*). The incidence of side effects is shown in accordance with the following scale: very often:> 10%; often:> 1% and <10%; infrequently:> 0.1% and <1%; rarely:> 0.01% and <0.1%; very rarely: <0.01%

Disorders of the psyche: Often: anxiety, insomnia, anxiety;

Infrequently: depression *;

Impaired nervous system:

Often, extrapyramidal disorders, akathisia, tremor, dizziness, drowsiness, sedation, headache;

Disorders from the side of the organ of vision:

Often: blurred vision;

Violations from the heart and vascular system:

Infrequently: tachycardia *, orthostatic hypotension *;

Disorders from the digestive system:

Often: indigestion, vomiting, nausea, constipation, drooling;

Systemic disorders and complications at the site of administration:

Often: fatigue.

Other observations:

In the treatment of aripiprazole schizophrenia, manic episodes and type I bipolar disorder, there was a lower incidence of extrapyramidal symptoms (EPS), including parkinsonism, than in patients treated with haloperidol and was the same as in patients receiving olanzapine.

The frequency of EPS in patients who received aripiprazole for manic episodes and type I bipolar disorder, was higher in comparison with the lithium drug treatment group.

Post-marketing application:

Spontaneous reports of adverse reactions are given below. Based on the available data, it is impossible to determine the frequency of occurrence of these effects.

Violations from the blood and lymphatic system:

Leukopenia, neutropenia, thrombocytopenia;

Immune disorders:

Allergic reactions (anaphylactic reactions, angioedema, including swelling and swelling of the tongue, swelling of the face, skin itching, urticaria);

Disorders from the endocrine system:

Hypercalcemia, diabetes mellitus, diabetic ketoacidosis, diabetic ketoosmolar coma;

Metabolic and nutritional disorders:

Weight gain, weight loss, anorexia, hyponatremia;

Disorders of the psyche: Agitation, nervousness; Suicidal attempts, suicidal thoughts, perfect suicide;

Impaired nervous system:

Violation of speech, malignant neuroleptic syndrome, epileptic seizure;

Violations from the heart and the vascular system:

Interval lengthening QT, ventricular arrhythmia, sudden death for unknown reasons, angina attack, polymorphic ventricular pirouette tachycardia, bradycardia, syncope, increased blood pressure, venous thromboembolism (including thromboembolism of the pulmonary arteries and deep vein thrombosis);

Disturbances from the respiratory system, chest and mediastinal organs: Oropharyngeal spasm, laryngospasm, aspiration pneumonia;

Disorders from the digestive system:

Pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhea;

Disorders from the hepatobiliary system:

Jaundice, hepatitis, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gammaglutamyltransferase (GGT), alkaline phosphatase (alkaline phosphatase);

Disturbances from the skin and subcutaneous tissue:

Rash, photodermatosis, alopecia, hyperhidrosis;

Disturbances from the musculoskeletal system and connective tissue:

Rhabdomyolysis, myalgia, stiffness;

Disorders from the urinary system:

Urinary incontinence, urinary retention;

Disorders from the reproductive system and mammary glands:

Priapism;

Pregnancy, postpartum period, perinatal conditions:

Syndrome of drug discontinuation in newborns;

Systemic disorders and complications at the site of administration:

Disorders of temperature regulation (hypothermia, pyrexia), chest pain, peripheral edema;

Research: Increase the activity of creatine phosphokinase, increase blood sugar concentration, fluctuate blood sugar concentration, increase the concentration of glycosylated hemoglobin.

Overdose:

During clinical studies and post-marketing applications were cases intentional or unintentional use of the drug adult patients at doses up to 1260 mg, not accompanied by death.

Symptoms: lethargy, increased blood pressure, tachycardia, nausea, vomiting, diarrhea, drowsiness. There have been reported cases of overdose of aripiprazole in children (up to 195 mg), not accompanied by a fatal outcome. Potentially dangerous overdose symptoms included drowsiness, transient loss of consciousness, extrapyramidal disorders. Treatment: Activated carbon (50 g, administered 1 hour after administration of aripiprazole, reduced the area under the curve "concentration-time" (AUC) and Cmaripiprazole 51% and 41%, respectively), maintenance therapy, adequate airway patency, oxygenation, effective ventilation and symptomatic treatment. Control of indicators of cardiovascular system function with registration of electrocardiogram for the detection of arrhythmias. It should be carefully monitored before all symptoms disappear.

The effectiveness of hemodialysis is unlikely (almost not excreted by the kidneys in an unchanged form and is largely associated with plasma proteins).

Interaction:

In connection with the inherent antipiprazole antagonism of a1-adrenergic receptors, there is a possibility of enhancing the effect of some antihypertensive agents.

Because the aripiprazole has an effect on the central nervous system (CNS), one should be afraid of simultaneous intake of alcohol or other drugs that affect the central nervous system, as this can lead to increased side effects, for example, sedation.

There was no significant effect of the H2-blocker of histodyne receptors of famotidine, which causes potent inhibition of hydrochloric acid secretion in the stomach, and the pharmacokinetics of aripiprazole.

Caution should be exercised when using aripiprazole with medications that may cause lengthening of the interval QT.

Various routes of metabolism of aripiprazole are known, including with the participation of isoenzymes CYP2D6 and CYP3A4. In studies in healthy people, powerful inhibitors isoenzyme CYP2D6 (quinidine) and isoenzyme CYP3A4 (ketoconazole) reduced the clearance of aripiprazole when administered by 52% and 38%, respectively. Therefore, the dose of aripiprazole should be reduced when used in combination with isozyme inhibitors CYP3A4 (itraconazole and HIV protease inhibitors) and CYP2D6. After the cancellation of isozyme inhibitors CYP3A4 and CYP2D6 the dose of aripiprazole should be returned to the original one.

When using aripiprazole with weak inhibitors of isoenzymes CYP3A4 (diltiazem, escitalopram) or CYP2D6, a small increase in the serum concentration of aripiprazole should be expected.

Receiving 30 mg of aripiprazole together with carbamazepine, a powerful isoenzyme inducer CYP3A4, was accompanied by a decrease of 68% and 73% Cmah and the area under the curve "concentration - time" (AUC) aripiprazole, respectively, and a decrease of 69% and 71% Cmah and the area under the curve "concentration - time" (AUC) its active metabolite dehydroaripiprazole, respectively. When using aripiprazole together with carbamazepine, a dose of aripiprazole should be doubled. You can expect a similar action and other powerful inductors of isoenzymes CYP3A4 (rifampicin, rifabutin, phenytoin, phenobarbital, primidon, efavirenz, nevirapine, St. John's wort pitted) and CYP2D6. After the cancellation of powerful isoenzyme inducers CYP3A4 and CYP2D6 The dose of aripiprazole should be reduced to the recommended dose.

In the metabolism of aripiprazole in vitro does not participate isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1, in connection with which it is unlikely that it interacts with drugs and other factors (for example, smoking), capable of inhibiting or activating these enzymes.

Simultaneous administration of lithium or valproate with aripiprazole did not have a clinically significant effect on the pharmacokinetics of aripiprazole.

In clinical trials aripiprazole in doses of 10-30 mg / day had no significant effect on the metabolism of substrates of isoenzymes CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin) and CYP3A4 (dextromethorphan). Besides, aripiprazole and its main metabolite dehydroaripiprazole did not alter the metabolism involving isoenzyme CYP1A2 in vitro. The clinically significant effect of aripiprazole on drugs metabolized with the participation of these isoenzymes is unlikely.

Simultaneous reception of lithium, lamotrigine or valproate with aripiprazole does not lead to clinically significant changes in the concentrations of lithium, lamotrigine or valproate.

Special instructions:

Since the improvement of the patient's condition in the treatment with neuroleptics may take several days, patients should be closely monitored.

Propensity to suicidal thoughts and attempts, characteristic for psychoses, can arise in a short time after the beginning of treatment or a drug change. Therefore, such patients should be carefully observed.

Disorders from the cardiovascular system: aripiprazole should be used with caution in patients with diseases of the cardiovascular system (myocardial infarction or ischemic heart disease in history, heart failure, conduction disorders), cerebrovascular disorders, risk factors for arterial hypotension (dehydration, hypovolemia, antihypertensive medication), arterial hypertension, including progressive and malignant. When using neuroleptics, vein thrombosis can develop. Since patients receiving antipsychotics may have predisposing factors to vein thromboembolism, a thorough examination of patients prior to treatment with aripiprazole should be carried out and preventive measures taken during treatment.

Conductivity disorders: interval lengthening frequency QT when treated with aripiprazole corresponds to that with placebo. However, in patients with a family history of lengthening the interval QT The same caution should be observed when administering aripiprazole, as with other neuroleptics.

Late dyskinesia: the risk of developing tardive dyskinesia increases with the duration of therapy with neuroleptics,so when you see symptoms of tardive dyskinesia during treatment, you should reduce the dose or cancel the drug. After the withdrawal of therapy, these symptoms may temporarily increase or even appear for the first time.

Malignant neuroleptic syndrome: when treating with neuroleptics, development of a life-threatening malignant neuroleptic syndrome (hyperpyrexia, muscle rigidity, mental disorders and instability of the autonomic nervous system, including pulse and arterial instability, tachycardia, sweating and arrhythmias) is possible. In addition, sometimes it is possible to increase the activity of creatine phosphokinase, the occurrence of myoglobinuria (rhabdomyolysis) and acute renal failure. In case of symptoms of malignant neuroleptic syndrome or unexplained fever, the drug should be canceled.

Convulsive seizures: When treating aripiprazole, cases of convulsive seizures were noted. Therefore, care should be taken when treating patients with seizures in history or suffering from disorders in which they can develop.

Elderly patients with senile dementia: the drug is not approved for the treatment of senile psychoses, as the risk of death increases and development cerebrovascular complications.

Hyperglycemia and diabetes mellitus: Hyperglycemia (in some cases expressed, with ketoacidosis), which can lead to hyperosmolar coma and even death, was noted in patients taking atypical antipsychotics. Although the relationship between the admission of atypical antipsychotics and hyperglycemia remains unclear, patients who have diabetes mellitus should regularly be assessed for blood glucose when taking atypical antipsychotics. Patients with risk factors for diabetes mellitus (obesity, the presence of diabetes in the family history) with the admission of atypical antipsychotics should be conducted to determine the concentration of glucose in the blood at the beginning of the course and periodically in the process of taking the drug. All patients taking atypical antipsychotics need constant monitoring of symptoms of hyperglycemia, including increased thirst, frequent urination, polyphagia, and weakness.

Hypersensitivity: as well as other medications, aripiprazole may cause hypersensitivity reactions.

Weight gain: There was no evidence of the effect of aripiprazole on weight gain.

Dysphagia: reception of antipsychotics, including aripiprazole, causes a violation of esophageal motility and aspiration. Patients with risk of aspiration pneumonia aripiprazole and other antipsychotics should be used with caution. Lactose intolerance: the drug contains lactose, so it should not be taken to patients with such rare hereditary diseases as galactose intolerance, lactase Lappa deficiency, or with glucose-galactose malabsorption syndrome.

Effect on the ability to drive transp. cf. and fur:

During the period of treatment, care must be taken when engaging in activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Pills 10 mg, 15 mg, 20 mg and 30 mg.

Packaging:

For 15 tablets with a dosage of 10 mg, 15 mg, 20 mg and 30 mg in a contiguous cell package from a combined three-layered material polyamide / aluminum / polyvinyl chloride (PA/A1/PVC) and aluminum foil.

For 1 or 2 contour packagings together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

In dry, the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001756

Date of registration:02.07.2012

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER-RUS, CJSC Russia

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp02.07.2012

Illustrated instructions

Instructions

Amdoal® (Amdoal®)