Amdoal, tablets 10 mg 30 pcs

Pharmgroup:

An antipsychotic drug (neuroleptic).

Pharmic action:

Amdoal is an antipsychotic drug (neuroleptic). The therapeutic effects of aripiprazole in schizophrenia are thought to be due to a combination of partial agonist activity against D2-dopamine and 5NT1a-serotonin receptors and antagonist activity against 5NT2-serotonin receptors.

Aripiprazole has high in vitro affinity for D2- and D3-dopamine receptors, 5NT1a- and 5NT2a-serotonin receptors and moderate affinity for D4-dopamine, 5NT2c and 5NT7-serotonin, α1-adrenoreceptors and H1-histamine receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and lack of affinity for muscarinic receptors. In animal experiments, aripiprazole exhibited antagonism to dopaminergic hyperactivity and agonism to dopaminergic hypoactivity. Interaction not only with dopamine and serotonin receptors explains some of the clinical effects of aripiprazole.

Pharmacokinetics: Aripiprazole is rapidly absorbed after oral administration. Food intake has no effect on the bioavailability of aripiprazole. Absolute bioavailability with oral administration is 87%. Cmax of aripiprazole in plasma is reached after 3-5 hours. Css is reached after 14 days.

Aripiprazole is intensely distributed in tissues, apparent Vd of 4.9 l/kg. The pharmacokinetic parameters of aripiprazole in equilibrium are proportional to the dose. At a therapeutic concentration of more than 99% aripiprazole is bound to plasma proteins, mainly to albumin. The main metabolite of aripiprazole, dehydroapiprazole, has the same affinity for D2-dopamine receptors as aripiprazole. No diurnal variations in the distribution of aripiprazole and its metabolite dehydroripiprazole have been observed. The equilibrium AUC of dehydroapiprazole is 39% of the AUC of aripiprazole in blood plasma.

It is slightly subjected to presystemic metabolism. Aripiprazole is the main component of the drug in plasma. Aripiprazole is metabolized in the liver by dehydrogenation, hydroxylation and N-dealkylation. In vitro dehydrogenation and hydroxylation of aripiprazole occurs with participation of CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation – with participation of CYP3A4 isoenzyme.

The mean T1/2 is approximately 75 h in fast CYP2D6 isoenzyme metabolizers and approximately 146 h in slow metabolizers. Total clearance of aripiprazole is 0.7 ml/min/kg, mainly due to excretion by the liver. After a single dose of 14C-labeled aripiprazole, approximately 27% of the dose was excreted by the kidneys and approximately 60% through the intestine. Less than 1% of the unchanged aripiprazole was detected in the urine and approximately 18% of the administered dose was excreted unchanged through the intestine.

Pharmacokinetics in special clinical cases:

With correction for body weight, the pharmacokinetics of aripiprazole and dehydroapiprazole in adolescents 13-17 years old were consistent with those in adults.

There were no differences in the pharmacokinetics of aripiprazole in elderly and adult healthy volunteers. There was also no effect of age on pharmacokinetics in patients with schizophrenia.

There are no differences in pharmacokinetics in healthy men and women. There is also no effect of sex on the pharmacokinetics of aripiprazole in patients with schizophrenia.

The studies found no clinically significant effect of racial differences or the effect of smoking on aripiprazole pharmacokinetics.
Similar pharmacokinetic parameters of aripiprazole and dihydroapiprazole were found in patients with severe kidney disease and in young healthy volunteers.

In patients with various degrees of cirrhosis (Child-Pugh grades A, B and C) after a single administration of aripiprazole, no significant effect of hepatic dysfunction on the pharmacokinetics of aripiprazole and dihydroxyprazole was found. Due to insufficient data in patients with decompensated cirrhosis (Child-Pugh grade C), definitive conclusions about metabolic activity cannot be drawn.

Indications

– treatment of schizophrenia in adults;
– treatment of manic episodes as part of bipolar I disorder and prevention of manic episodes in patients who have a history of manic episodes and have had a clinical response to treatment with aripiprazole.

Pharmacological effect

Pharmaceutical group:

Antipsychotic drug (neuroleptic).

Pharmaceutical action:

Amdoal is an antipsychotic drug (neuroleptic). The therapeutic effect of aripiprazole in schizophrenia is believed to be due to a combination of partial agonist activity at D2-dopamine and 5HT1a-serotonin receptors and antagonistic activity at 5HT2-serotonin receptors.

Aripiprazole has high in vitro affinity for D2- and D3-dopamine receptors, 5HT1a- and 5HT2a-serotonin receptors and moderate affinity for D4-dopamine, 5HT2c- and 5HT7-serotonin receptors, α1-adrenergic receptors and H1-histamine receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and lack of affinity for muscarinic receptors. In animal experiments, aripiprazole exhibited antagonism against dopaminergic hyperactivity and agonism against dopaminergic hypoactivity. Interaction not only with dopamine and serotonin receptors explains some of the clinical effects of aripiprazole.

Pharmacokinetics: Aripiprazole is rapidly absorbed after oral administration. Food intake does not affect the bioavailability of aripiprazole. Absolute bioavailability when taken orally is 87%. Cmax of aripiprazole in plasma is achieved after 3-5 hours. Css is achieved after 14 days.

Aripiprazole is intensively distributed in tissues, the apparent Vd is 4.9 l/kg. The pharmacokinetics of aripiprazole at steady state are proportional to the dose. At therapeutic concentrations of more than 99% of aripiprazole is bound to plasma proteins, mainly albumin. The main metabolite of aripiprazole, dehydroaripiprazole, has the same affinity for D2-dopamine receptors as aripiprazole. There were no daily fluctuations in the distribution of aripiprazole and its metabolite dehydroaripiprazole. The steady-state AUC of dehydroaripiprazole is 39% of the plasma AUC of aripiprazole.

Slightly undergoes first-pass metabolism. Aripiprazole is the main component of the drug in blood plasma. Aripiprazole is metabolized in the liver by dehydrogenation, hydroxylation and N-dealkylation. In vitro, dehydrogenation and hydroxylation of aripiprazole occurs with the participation of the CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation occurs with the participation of the CYP3A4 isoenzyme.

The average T1/2 is approximately 75 hours for rapid metabolizers of the CYP2D6 isoenzyme and approximately 146 hours for slow metabolizers. The total clearance of aripiprazole is 0.7 ml/min/kg, mainly due to excretion by the liver. Following a single dose of 14C-labeled aripiprazole, approximately 27% of the dose was excreted by the kidneys and approximately 60% by the intestine. Less than 1% of unchanged aripiprazole is determined in the urine and approximately 18% of the dose taken is excreted unchanged through the intestines.

Pharmacokinetics in special clinical situations:

Taking into account adjustment for body weight, the pharmacokinetics of aripiprazole and dehydroaripiprazole in adolescents 13-17 years of age corresponded to those in adults.

There were no differences in the pharmacokinetics of aripiprazole in elderly and adult healthy volunteers. There was also no effect of age on pharmacokinetics in patients with schizophrenia.

There are no differences in pharmacokinetics between healthy men and women. There was also no effect of gender on the pharmacokinetics of aripiprazole in patients with schizophrenia.

The studies did not reveal a clinically significant effect of race or smoking on the pharmacokinetics of aripiprazole.
The same pharmacokinetic parameters of aripiprazole and dihydroaripiprazole were found in patients with severe kidney disease and in young healthy volunteers.

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

Special instructions

Since patient improvement with antipsychotic treatment may take several days, patients should be closely monitored. Tendency to suicidal thoughts and attempts, characteristic of psychosis, can occur within a short time after starting treatment or changing the drug. Therefore, such patients should be carefully monitored.

Violations by the SSS. Aripiprazole should be used with caution in patients with cardiovascular diseases (myocardial infarction or coronary artery disease in history, heart failure, conduction disorders), cerebrovascular disorders, risk factors for the development of arterial hypotension (dehydration, hypovolemia, taking antihypertensive drugs), arterial hypertension, including progressive and malignant.

When using antipsychotics, venous thrombosis may develop. Because patients receiving antipsychotics may have predisposing factors for venous thromboembolism, patients should be carefully assessed before initiating treatment with aripiprazole and preventive measures should be taken during treatment.

Conduction disorders. The incidence of QT prolongation with aripiprazole is similar to that with placebo. However, in patients with a family history of QT prolongation, the same caution should be used when prescribing aripiprazole as when using other antipsychotics.

Tardive dyskinesia. The risk of developing tardive dyskinesia increases with the duration of antipsychotic therapy, therefore, if symptoms of tardive dyskinesia appear during treatment, the dose should be reduced or the drug discontinued. After discontinuation of therapy, these symptoms may temporarily intensify or even appear for the first time.

Neuroleptic malignant syndrome. When treated with antipsychotics, the development of life-threatening malignant neuroleptic syndrome (hyperpyrexia, muscle rigidity, mental disorders and instability of the autonomic nervous system, including instability of pulse and blood pressure, tachycardia, sweating and arrhythmias) is possible. In addition, it is sometimes possible to increase CPK activity, causing myoglobinuria (rhabdomyolysis) and acute renal failure. If symptoms of neuroleptic malignant syndrome or unexplained fever occur, the drug should be discontinued.

Convulsive seizures. Cases of seizures have been reported during treatment with aripiprazole. Therefore, caution should be exercised when treating patients with a history of seizures or disorders in which they may develop.

Elderly patients suffering from senile dementia. The drug is not approved for the treatment of senile psychoses, because the risk of mortality and development of cerebrovascular complications increases.

Hyperglycemia and diabetes mellitus. Hyperglycemia (in some cases severe, with ketoacidosis), which can lead to hyperosmolar coma and even death, has been noted in patients taking atypical antipsychotics. Although the relationship between the use of atypical antipsychotics and hyperglycemia remains unclear, patients diagnosed with diabetes mellitus require regular monitoring of blood glucose concentrations while taking atypical antipsychotics. In patients with risk factors for diabetes mellitus (obesity, family history of diabetes mellitus), when taking atypical antipsychotics, it is necessary to determine the concentration of glucose in the blood at the beginning of the course and periodically while taking the drug. In all patients taking atypical antipsychotics, constant monitoring of symptoms of hyperglycemia, including increased thirst, frequent urination, polyphagia, and weakness is necessary.

Hypersensitivity. Like other medicines, aripiprazole may cause hypersensitivity reactions.

Increased body weight. There was no effect of aripiprazole on weight gain.

Dysphagia. Antipsychotic medications, including aripiprazole, have been associated with esophageal dysmotility and aspiration. Aripiprazole and other antipsychotics should be used with caution in patients at risk for aspiration pneumonia.

Lactose intolerance. The drug contains lactose, so it should not be taken by patients with rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and operate machinery. During the treatment period, care must be taken when engaging in activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Aripiprazole

Composition

1 tablet contains:

active substance:

aripiprazole 10 mg,

excipients:

lactose monohydrate;

MCC;

corn starch;

hyprolose;

magnesium stearate.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Due to insufficient safety data, the drug can be taken during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. Patients should be warned about the need to immediately inform the doctor about the occurrence of pregnancy during treatment with aripiprazole, as well as about planned pregnancy.

Newborns whose mothers took antipsychotics during the third trimester of pregnancy are at risk of developing extrapyramidal disorders and/or withdrawal syndrome in the postpartum period. Newborns experienced agitation, increased or decreased blood pressure, tremor, drowsiness, respiratory distress syndrome, and feeding disturbances. Such newborns need careful monitoring.

During treatment with aripiprazole, it is recommended to discontinue breastfeeding. Animal studies have provided data on the excretion of the drug in milk. There is no data on the penetration of aripiprazole into breast milk.

Contraindications

hypersensitivity to one of the components of the drug;
senile dementia;
lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
lactation period;
age up to 18 years.

With caution: cardiovascular diseases (coronary heart disease, including previous myocardial infarction, chronic heart failure, conduction disturbances; conditions predisposing to a decrease in blood pressure (dehydration, hypovolemia, taking antihypertensive drugs) due to the possibility of developing orthostatic hypotension; cerebrovascular diseases; epilepsy; diseases in which the development of seizures is possible; patients at risk of developing aspiration pneumonia (due to the risk of impaired motor function of the esophagus and aspiration); patients with an increased risk of hyperthermia, for example, during intense physical activity, overheating, taking drugs with m-anticholinergic activity, and dehydration (due to the ability of antipsychotics to disrupt thermoregulation); patients with a history of diabetes;

Side Effects

From the mental side: often – anxiety, insomnia, restlessness; infrequently – depression*.

From the nervous system: often – extrapyramidal disorders, akathisia, tremor, dizziness, drowsiness, sedation, headache.

From the side of the organ of vision: often – blurred vision.

From the heart and vascular system: infrequently – tachycardia*, orthostatic hypotension*.

From the digestive system: often – dyspepsia, vomiting, nausea, constipation, drooling.

Systemic disorders and complications at the injection site: often – fatigue.

Other observations: When treated with aripiprazole for schizophrenia, manic episodes and bipolar I 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 treated with olanzapine. The incidence of EPS in patients treated with aripiprazole for manic episodes and bipolar I disorder was higher compared with the lithium group.

Post-marketing use

The following are spontaneous reports of adverse reactions. Based on the available data, it is not possible to determine the frequency of occurrence of these effects.

Blood and lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia.

Immune disorders: allergic reactions (anaphylactic reactions, angioedema, including swelling and swelling of the tongue, swelling of the face, itching, urticaria).

From the endocrine system: hypercalcemia, diabetes mellitus, diabetic ketoacidosis, diabetic keto-osmolar coma.

Metabolism and nutrition: weight gain, weight loss, anorexia, hyponatremia.

From the mental side: agitation, nervousness; suicide attempts, suicidal thoughts, completed suicide.

From the nervous system: speech impairment, neuroleptic malignant syndrome, epileptic seizure.

From the heart and vascular system: prolongation of the QT interval, ventricular arrhythmia, sudden death of an unknown cause, angina attack, polymorphic ventricular tachycardia of the “pirouette” type, bradycardia, fainting, increased blood pressure, venous thromboembolism (including thromboembolism of the branches of the pulmonary artery and deep vein thrombosis).

From the respiratory system, chest and mediastinal organs: oropharyngeal spasm, laryngospasm, aspiration pneumonia;

From the digestive system: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhea.

From the hepatobiliary system: jaundice, hepatitis, increased activity of ALT, AST, GGT, alkaline phosphatase.

From the musculoskeletal system and connective tissue: rhabdomyolysis, myalgia, rigidity.

From the urinary system: urinary incontinence, urinary retention.

From the reproductive system and mammary glands: priapism.

Pregnancy, postpartum period, perinatal conditions: drug withdrawal syndrome in newborns.

Systemic disorders and complications at the injection site: temperature regulation disorders (hypothermia, pyrexia), chest pain, peripheral edema.

Laboratory tests: increased CPK activity, increased blood sugar concentration, fluctuations in blood sugar concentration, increased concentration of glycosylated hemoglobin.

Interaction

Due to the inherent antagonism of aripiprazole to α1-adrenergic receptors, there is a possibility of enhancing the effect of some antihypertensive drugs. Since aripiprazole has an effect on the central nervous system, one should be wary of concomitant use of alcohol or drugs that affect the central nervous system, because this may result in increased side effects such as sedation. There was no significant effect of the H2-blocker of histamine receptors famotidine, which causes a powerful inhibition of hydrochloric acid secretion in the stomach, on the pharmacokinetics of aripiprazole.

Caution should be exercised when using aripiprazole with drugs that may cause QT prolongation.

Various pathways of metabolism of aripiprazole are known, incl. with the participation of isoenzymes CYP2D6 and CYP3A4. In studies in healthy people, potent inhibitors of CYP2D6 (quinidine) and CYP3A4 (ketoconazole) reduced the oral clearance of aripiprazole by 52 and 38%, respectively. Therefore, the dose of aripiprazole should be reduced when used in combination with inhibitors of CYP3A4 isoenzymes (itraconazole and HIV protease inhibitors) and CYP2D6. After discontinuation of inhibitors of CYP3A4 and CYP2D6 isoenzymes, the dose of aripiprazole should be returned to the original dose.

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

Taking 30 mg of aripiprazole together with carbamazepine, a strong inducer of the CYP3A4 isoenzyme, was accompanied by a 68 and 73% decrease in the Cmax and AUC of aripiprazole, respectively, and a 69 and 71% decrease in the Cmax and AUC of its active metabolite dehydroaripiprazole, respectively. When using aripiprazole with carbamazepine, the aripiprazole dose should be doubled. A similar effect can be expected with other powerful inducers of CYP3A4 isoenzymes (rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, St. John’s wort) and CYP2D6. After discontinuation of potent inducers of the CYP3A4 and CYP2D6 isoenzymes, reduce the dose of aripiprazole to the recommended dose. The in vitro metabolism of aripiprazole does not involve the isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1, and therefore its interaction with drugs and other factors (for example smoking) that can inhibit or activate these enzymes is unlikely.

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

In clinical studies, aripiprazole in doses of 10–30 mg/day did not have a significant effect on the metabolism of the substrates of the isoenzymes CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole, warfarin) and CYP3A4 (dextromethorphan). In addition, aripiprazole and its main metabolite dehydroaripiprazole did not alter CYP1A2 metabolism in vitro. A clinically significant effect of aripiprazole on drugs metabolized by these isoenzymes is unlikely.

Concomitant use of lithium, lamotrigine or valproate with aripiprazole does not lead to a clinically significant change in the concentrations of lithium, lamotrigine or valproate.

Overdose

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

Symptoms: lethargy, increased blood pressure, tachycardia, nausea, vomiting, diarrhea, drowsiness.

Cases of aripiprazole overdose in children (up to 195 mg), which were not accompanied by death, have been described.

Symptoms: drowsiness, transient loss of consciousness, extrapyramidal disorders.

Treatment: administration of activated charcoal (50 g administered 1 hour after taking aripiprazole reduced the AUC and Cmax of aripiprazole by 51 and 41%, respectively), supportive care, ensuring adequate airway patency, oxygenation, effective ventilation and symptomatic treatment; monitoring of cardiovascular function indicators with ECG registration to detect arrhythmias. Careful medical observation should be carried out until all symptoms disappear.

The effectiveness of hemodialysis is unlikely (it is practically not excreted unchanged by the kidneys and is largely bound to plasma proteins).

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 30 °C

Shelf life

3 years

Manufacturer

Gedeon Richter-RUS, Russia