Amdoal, tablets 15 mg 30 pcs

Amdoal is a neuroleptic.

Pharmacodynamics

The therapeutic effect of aripiprazole in schizophrenia is due to a combination of partial agonist activity against D₂-dopamine and 5NT_1a-serotonin receptors and antagonistic activity against 5NT₂-serotonin receptors.

Aripiprazole has high in vitro affinity for D₂– and D_Z-dopamine receptors, 5NT_1a– and 5NT_2a-serotonin receptors and moderate affinity for D₄-dopamine, 5NT_2c– and 5NT₇-serotonin, α_l-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%. C_max of aripiprazole in plasma is reached after 3-5 hours. C_ss is reached after 14 days.

Distribution

Aripiprazole is intensely distributed in tissues, V_d is 4.9 l/kg. The pharmacokinetics of aripiprazole in equilibrium is proportional to the dose. At a therapeutic concentration, more than 99% of 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.

Metabolism

It is slightly subjected to presystemic metabolism. Aripiprazole is the major 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 occur with participation of CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation – with participation of CYP3A4 isoenzyme.

Elevation

The T_1/2 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% by the intestine. Less than 1% of the unchanged aripiprazole was detected in the urine and approximately 18% of the unchanged dose was excreted through the intestine.

Particular groups of patients

Children. Adjusted for body weight, the pharmacokinetics of aripiprazole and dehydroapiprazole in adolescents 13-17 years of age were consistent with those in adults.

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

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

Smoking and race. Studies have found no clinically significant effect of racial differences or effect of smoking on aripiprazole pharmacokinetics.

Kidney disease. The pharmacokinetics of aripiprazole and dihydroapiprazole were found to be similar in patients with severe kidney disease and young healthy volunteers.

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

Indications

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

Active ingredient

Composition

1 tablet contains:

the active ingredient:

aripiprazole 15 mg,

excipients:

lactose monohydrate;

MCC;

Corn starch;

Hyprolose;

Magnesium stearate.

How to take, the dosage

Overly, once a day, regardless of meals.

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

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

Prevention of manic episodes in bipolar disorder type I. To prevent manic episodes in patients who have previously taken aripiprazole as monotherapy or in combination, continue treatment at the same dose. Adjustment of the daily dose, including its reduction, is made according to the patient’s condition.

Patient special groups

Patients with renal insufficiency. No dose adjustment is required when prescribing the drug in patients with renal impairment.

Patients with hepatic impairment. No dose adjustment is required when administering the drug to patients with renal failure. However, the daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.

Patients over 65 years of age. No dose adjustment is required.

The effect of gender on the dosing regimen. The dosing regimen of the drug is the same for patients of both sexes.

Dosages in concomitant therapy. In concomitant use of the drug Amdoal® and potent inhibitors of CYP2D6 or CYP3A4 isoenzymes the dose of Amdoal® should be reduced by half. If CYP2D6 or CYP3A4 isoenzyme inhibitors are cancelled, the dose of Amdoal® should be increased. Amdoal® should be used without dosing changes if it is prescribed as adjunctive therapy in patients with major depressive disorder. When concomitant use of Amdoal® and CYP3A4 isoenzyme inducers, the dose of Amdoal® should be doubled. Additional increase in the dose of the drug Amdoal® should be made taking into account clinical indications. If CYP3A4 isoenzyme inducers are withdrawn, the dose of Amdoal® should be reduced. When several drugs inhibiting CYP2D6 and CYP3A4 isoenzymes are prescribed, the daily dose of Amdoal® should be considered.

Interaction

Due to the inherent antagonism of aripiprazole to αl adrenoreceptors, there is a possibility of enhancing the effect of some antihypertensive agents. Since aripiprazole affects the CNS, concomitant administration of alcohol or CNS-affecting drugs should be avoided because it may lead to increased side effects, such as sedation. No significant effect of H2-blocker of histamine receptors famotidine, which causes potent inhibition of gastric hydrochloric acid secretion, on aripiprazole pharmacokinetics was found.

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

There are different pathways of aripiprazole metabolism, including those involving CYP2D6 and CYP3A4 isoenzymes. In healthy human subjects studies the potent inhibitors of CYP2D6 isoenzyme (quinidine) and CYP3A4 isoenzyme (ketoconazole) decreased aripiprazole clearance by 52 and 38% accordingly in oral administration. Therefore, the dose of aripiprazole should be reduced when used in combination with CYP3A4 isoenzyme inhibitors (itraconazole and HIV protease inhibitors) and CYP2D6. After withdrawal of the CYP3A4 and CYP2D6 isoenzyme inhibitors, the dose of aripiprazole should be returned to the initial dose.

When aripiprazole is used with weak CYP3A4 isoenzyme inhibitors (diltiazem, escitalopram) or CYP2D6, a slight increase in serum concentration of aripiprazole should be expected.

The administration of 30 mg of aripiprazole together with carbamazepine, a potent inducer of the CYP3A4 isoenzyme, was accompanied by a 68% and 73% decrease in Cmax and AUC of aripiprazole, respectively, and a 69% and 71% reduction in Cmax and AUC of its active metabolite dehydroapiprazole, respectively. When using aripiprazole together with carbamazepine, the dose of aripiprazole should be doubled. Other potent inducers of CYP3A4 isoenzymes (rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, St. John’s wort) and CYP2D6 can be expected to have similar effects. After withdrawal of potent inducers of CYP3A4 and CYP2D6 isoenzymes, the dose of aripiprazole should be reduced to the recommended dose. Isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2E1 are not metabolized in vitro, in this connection interactions with drugs and other factors (for example, smoking) which can inhibit or activate these enzymes are unlikely.

The concomitant administration of lithium or valproate with aripiprazole had no clinically significant effect on the pharmacokinetics of aripiprazole.

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

The concomitant administration of lithium, lamotrigine or valproate with aripiprazole does not result in clinically significant changes in concentrations of lithium, lamotrigine or valproate.

Special Instructions

Since patient improvement with neuroleptic treatment may take several days, patients should be closely monitored. The propensity for suicidal thoughts and attempts characteristic of psychosis can occur shortly after starting treatment or changing medication. Therefore, these patients should be closely monitored.

Systemic abnormalities. Aripiprazole should be used with caution in patients with cardiac diseases (history of myocardial infarction or CHD, heart failure, conduction disorders), cerebrovascular disorders, risk factors for arterial hypotension (dehydration, hypovolemia, taking antihypertensive drugs), arterial hypertension, including progressive and malignant.

Venous thrombosis may develop with the use of neuroleptics. Because patients receiving neuroleptics may have predisposing factors to venous thromboembolism, patients should be carefully evaluated before treatment with aripiprazole and preventive measures should be taken during treatment.

Conduction disorders. The incidence of QT interval prolongation during treatment with aripiprazole is consistent with that during placebo administration. However, in patients with a family history of QT interval prolongation, the same caution should be exercised when prescribing aripiprazole as with other neuroleptics.

Late dyskinesia. The risk of developing tardive dyskinesia increases with the duration of neuroleptic therapy, so if symptoms of tardive dyskinesia appear during treatment, the dose should be reduced or the drug withdrawn. After withdrawal of therapy, these symptoms may increase temporarily or even appear for the first time.

Malignant neuroleptic syndrome. Treatment with neuroleptics can lead to life-threatening malignant neuroleptic syndrome (hyperpyrexia, muscle rigidity, mental disturbances and autonomic nervous system instability, including pulse and BP instability, tachycardia, sweating and arrhythmias). In addition, sometimes there may be increased CPK activity, occurrence of myoglobinuria (rhabdomyolysis) and acute renal failure. If symptoms of malignant neuroleptic syndrome or unexplained fever occur, the drug should be withdrawn.

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

Elderly patients with senile dementia. The drug is not approved for the treatment of senile psychosis because of the increased risk of mortality and development of cerebrovascular complications.

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 neuroleptics. Although the association between taking atypical neuroleptics and hyperglycemia remains unclear, patients diagnosed with diabetes need regular monitoring of blood glucose concentrations while taking atypical neuroleptics. In patients with risk factors for diabetes mellitus (obesity, family history of diabetes mellitus), when taking atypical neuroleptics, blood glucose concentrations should be determined at the beginning of the course and periodically during the administration of the drug. In all patients taking atypical neuroleptics, continuous monitoring of symptoms of hyperglycemia, including increased thirst, frequent urination, polyphagia, and weakness, is necessary.

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

Body weight gain. No effect of aripiprazole on weight gain has been found.

Dysphagia. Administration of neuroleptics, including aripiprazole, causes disruption of esophageal motility and aspiration. In patients at 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 by patients with such rare hereditary diseases as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.

Impact on the ability to drive motor transport and operate machinery. During treatment, caution should be exercised when engaged in activities requiring increased concentration and rapid psychomotor reactions.

Contraindications

Side effects

Psychiatric disorders: often – anxiety, insomnia, anxiety; infrequently – depression*.

Nervous system disorders: often – extrapyramidal disorders, akathisia, tremor, dizziness, somnolence, sedation, headache.

An organ of vision: often – blurred vision.

Heart and vascular system disorders: infrequent – tachycardia*, orthostatic hypotension*.

Digestive system disorders: often – dyspepsia, vomiting, nausea, constipation, salivation.

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

Other observations: The incidence of extrapyramidal symptoms (EPS), including parkinsonism, was lower in aripiprazole-treated schizophrenia, manic episodes and type I bipolar disorder than in patients treated with haloperidol and was the same as in patients treated with olanzapine. The incidence of EPS was higher in patients treated with aripiprazole for manic episodes and type I bipolar disorder compared with the lithium treatment group.

Postmarketing use

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

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

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

Endocrine system disorders: hypercalcemia, diabetes, diabetic ketoacidosis, diabetic ketoosmolar coma.

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

Psychiatric disorders: agitation, nervousness; suicide attempts, suicidal thoughts, committed suicide.

Nervous system disorders: speech impairment, malignant neuroleptic syndrome, epileptic seizures.

Heart and vascular system disorders: prolongation of QT interval, ventricular arrhythmia, sudden death from unknown cause, angina attack, polymorphic ventricular tachycardia of pirouette type, bradycardia, syncope, BP increase, venous embolism (including pulmonary artery branch thromboembolism and deep vein thrombosis).

Respiratory system, chest and mediastinum: oropharyngeal spasm, laryngospasm, aspiration pneumonia;

Digestive system: pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhea.

Hepatobiliary system: jaundice, hepatitis, increased activity of ALT, AST, GGT, ALP.

Muscular system and connective tissue disorders: rhabdomyolysis, myalgia, rigidity.

Mineral system disorders: urinary incontinence, urinary retention.

Reproductive system and mammary glands: priapism.

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

Systemic disorders and complications at the site of administration: disorders of temperature regulation (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.

Overdose

In clinical trials and post-marketing use, cases of intentional or unintentional use of the drug in adult patients at doses up to 1260 mg have been found that were not fatal.

Symptoms: lethargy, increased BP, tachycardia, nausea, vomiting, diarrhea, drowsiness.

There have been described cases of aripiprazole overdose in children (up to 195 mg) that were not fatal.

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

Treatment: Administration of activated charcoal (50 g administered 1 h after aripiprazole reduced the AUC and Cmax of aripiprazole by 51 and 41%, respectively), supportive therapy, ensuring adequate airway patency, oxygenation, effective ventilation, and symptomatic treatment; monitoring of CPR with ECG recording to detect arrhythmias. Close medical monitoring should be maintained until all symptoms have resolved.

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

Pregnancy use

There have been no adequate and well-controlled studies in pregnant women.

Due to insufficient safety data, the drug may be taken during pregnancy only if the potential benefit to the mother exceeds the potential risk to the fetus.

Patients should be warned to inform their physician immediately about the occurrence of pregnancy during treatment with aripiprazole, as well as about the planned pregnancy. In neonates 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.

Newborns have been noted to have agitation, increased or decreased BP, tremors, somnolence, respiratory distress syndrome, and feeding disturbances. Such newborns need close monitoring.

Breastfeeding should be discontinued during treatment with aripiprazole. In animal studies data on excretion of the drug with milk have been obtained. There are no data on penetration of aripiprazole into breast milk.

Similarities