Arilental tablets 15 mg blister No. 28

Instructions for Arilental tablets 15 mg blister No. 28

Warehouse

active ingredient: aripiprazole;

1 tablet contains 10 mg or 15 mg of aripiprazole;

Excipients: microcrystalline cellulose (type 101); lactose monohydrate; corn starch; hydroxypropylcellulose; microcrystalline cellulose (type 102); magnesium stearate.

Dosage form

Pills.

Main physicochemical properties:

Arilental, tablets, 10 mg, No. 7 in a blister, 1 blister or 4 blisters in a pack: white, capsule-shaped, biconvex tablets, engraved with “10” on one side and “ZL” on the other;

Arilental, tablets, 15 mg, No. 7 in a blister, 1 blister or 4 blisters in a pack: white, round biconvex tablets, engraved with "15" on one side and "ZL" on the other.

Pharmacotherapeutic group

Agents acting on the nervous system. Psycholeptics. Antipsychotics. Other antipsychotics. Aripiprazole.

ATX code N05A X12.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Antipsychotic drug (neuroleptic). The therapeutic effect of aripiprazole in schizophrenia and bipolar I disorder is thought to be due to a combination of partial agonist activity at D2 dopamine and 5HT1A serotonin receptors and antagonist activity at 5HT2A serotonin receptors.

Aripiprazole has high affinity in vitro for D2 and D3 dopamine receptors, 5HT1A and 5HT2A serotonin receptors, and moderate affinity for D4 dopamine, 5HT2C and 5HT7 serotonin, α1-adrenoceptors, and histamine H1 receptors. Aripiprazole also has moderate affinity for serotonin reuptake sites and no affinity for muscarinic receptors.

Interactions with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

In experimental animal studies, aripiprazole exhibited antagonism towards dopaminergic hyperactivity and agonism towards dopaminergic hypoactivity.

Aripiprazole at doses ranging from 0.5 to 30 mg once daily in healthy volunteers for 2 weeks showed a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate nucleus and putamen, as measured by positron emission tomography.

Pharmacokinetics.

Absorption

After oral administration, aripiprazole is rapidly absorbed from the gastrointestinal tract (GI). Cmax in plasma is reached after 3–5 hours. Aripiprazole undergoes minimal first-pass metabolism. Absolute bioavailability is 87%. Intake of fatty food does not affect the pharmacokinetics of aripiprazole.

Distribution and metabolism

Aripiprazole is extensively distributed into tissues, with an apparent volume of distribution (Vd) of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, more than 99% of aripiprazole and dehydroaripiprazole are bound to serum proteins, primarily albumin.

It is extensively metabolized in the liver by three pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro, dehydrogenation and hydroxylation of aripiprazole occur under the action of CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation occurs under the action of CYP3A4.

The activity of Arilental is mainly due to the presence of unchanged aripiprazole in the systemic circulation.

At steady state, the AUC of dehydroaripiprazole in plasma is approximately 40% of the AUC of aripiprazole.

Breeding

The mean elimination half-life (T1/2) of aripiprazole is approximately 75 hours in CYP2D6 extensive metabolizers and approximately 146 hours in CYP2D6 poor metabolizers.

Following a single dose of 14C-labeled aripiprazole, approximately 27% and 60% of the radioactivity is recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole is recovered in the urine and approximately 18% of the administered dose is excreted unchanged in the feces. The total clearance of aripiprazole is 0.7 mL/min/kg, primarily by hepatic elimination.

Pharmacokinetics in special patient groups.

Children

The pharmacokinetics of aripiprazole and dehydroaripiprazole in patients aged 10 to 17 years were similar to those in adults after adjusting for differences in body weight.

Elderly patients

There are no differences in the pharmacokinetics of aripiprazole between healthy elderly volunteers and younger patients. There are no apparent differences in pharmacokinetics among different age groups in patients with schizophrenia.

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

Smoking

Population pharmacokinetic evaluation revealed no clinically significant smoking-related effect on the pharmacokinetics of aripiprazole.

Race

Population pharmacokinetic evaluation did not reveal clinically significant race-related differences in the pharmacokinetics of aripiprazole.

Kidney dysfunction

The pharmacokinetic characteristics of aripiprazole and dehydroaripiprazole were found to be similar in both patients with severe renal disease and young healthy volunteers.

In studies in patients with varying degrees of cirrhosis (Child-Pugh Class A, B, and C), there was no significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydroaripiprazole following single doses of aripiprazole. Due to the lack of data, definitive conclusions cannot be drawn about metabolic activity in patients with decompensated cirrhosis (Child-Pugh Class C).

Indication

Treatment of schizophrenia in adults.

Treatment of moderate to severe manic episodes in bipolar I disorder, and for the prevention of new manic episodes in adults who have previously had manic episodes and who have responded to treatment with aripiprazole.

Contraindication

Hypersensitivity to aripiprazole and other components of the drug.

Interaction with other medicinal products and other types of interactions

Due to antagonism at α1-adrenergic receptors, aripiprazole may enhance the effect of some antihypertensive drugs.

Since aripiprazole affects the central nervous system (CNS), caution should be exercised when alcohol or drugs that affect the CNS are taken concomitantly due to possible cross-reactions, such as sedation (see section 4.8).

Aripiprazole should be used with caution in combination with other drugs that prolong the QT interval or disrupt electrolyte balance.

Potential effects of other drugs on the action of aripiprazole.

The H2-histamine receptor blocker famotidine, which causes significant inhibition of gastric acid secretion, did not have a significant effect on the pharmacokinetics of aripiprazole, despite a decrease in the rate of absorption of aripiprazole.

Aripiprazole is metabolized by various pathways, including CYP2D6 and CYP3A4, but not CYP1A. Therefore, no dose adjustment is necessary for smokers.

Quinidine and other CYP2D6 inhibitors.

In healthy volunteers, a potent CYP2D6 inhibitor (quinidine) increased the AUC of aripiprazole by 107%, while Cmax remained unchanged. The AUC and Cmax of dehydroaripiprazole, the active metabolite, were decreased by 32% and 47%, respectively. Therefore, the dose of Aripiprazole should be reduced by approximately half when administered with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have a similar effect, and similar dose reductions are therefore required.

Ketoconazole and other CYP3A4 inhibitors.

In studies in healthy volunteers, a strong CYP3A4 inhibitor (ketoconazole) increased the AUC and Cmax of aripiprazole by 63% and 37%, respectively. The AUC and Cmax of dehydroaripiprazole increased by 77% and 43%, respectively. In individuals who are poor metabolizers of CYP2D6, concomitant administration of strong CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole compared to those in patients who are extensive metabolizers of CYP2D6.

If concomitant use of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefits should outweigh the potential risks to the patient. When aripiprazole and ketoconazole are co-administered, the aripiprazole dose should be reduced by approximately half. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, could theoretically have similar effects and therefore doses should be reduced accordingly (see section 4.2).

After discontinuation of the CYP2D6 or CYP3A4 inhibitor, the aripiprazole dose should be increased to the level used prior to initiation of concomitant therapy.

A small increase in aripiprazole plasma concentrations is possible with concomitant use of weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (escitalopram).

Carbamazepine and other CYP3A4 inducers.

Coadministration of 30 mg of aripiprazole with carbamazepine, a potent CYP3A4 inducer, was accompanied by a 68% and 73% decrease in the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of aripiprazole, respectively, and a 69% and 71% decrease in the Cmax and AUC of its active metabolite, dehydroaripiprazole, respectively, compared with the corresponding values for aripiprazole monotherapy.

The dose of aripiprazole should be doubled when co-administered with carbamazepine. Co-administration of aripiprazole with other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John's wort) is expected to have a similar effect, and an appropriate dose increase is therefore required. After discontinuation of potent CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended dose.

Valproate and lithium.

No clinically significant changes in aripiprazole concentrations were observed when lithium or valproate was co-administered with aripiprazole, so no dose adjustment is required.

Potential effects of aripiprazole on the effects of other drugs.

When aripiprazole was co-administered with valproate, lithium, or lamotrigine, no clinically significant changes in valproate, lithium, or lamotrigine concentrations were observed.

Serotonin syndrome.

Cases of serotonin syndrome have been reported in patients taking aripiprazole, particularly when used concomitantly with other serotonergic drugs such as SSRIs (selective serotonin/norepinephrine reuptake inhibitors) or with drugs that increase aripiprazole concentrations (see section 4.8).

Application features

With antipsychotic treatment, it may take several days to several weeks for the patient to achieve clinical improvement. During this period, patients should be closely monitored.

Suicide

The emergence of suicidal behaviour is common in patients with psychotic and mood disorders and has been observed in some cases early in antipsychotic treatment, including aripiprazole (see section 4.8). Antipsychotic treatment should be accompanied by close monitoring of patients at increased risk.

Tardive dyskinesia

Symptoms of tardive dyskinesia have been reported rarely in patients taking aripiprazole for up to one year. If symptoms of tardive dyskinesia develop in a patient taking aripiprazole, dose reduction or discontinuation of treatment should be considered (see section 4.8). These symptoms may temporarily worsen or even recur after discontinuation of treatment.

Other extrapyramidal symptoms.

Akathisia and parkinsonism have been observed in children with aripiprazole. If signs of other extrapyramidal symptoms appear, dose reduction should be considered and the patient should be closely monitored clinically.

Neuroleptic malignant syndrome (NMS).

NMS is a potentially fatal symptom complex associated with the use of antipsychotic drugs. In clinical trials with aripiprazole, cases of NMS were rare. This syndrome has the following clinical manifestations: hyperpyrexia (extremely high body temperature), muscle rigidity, altered mental status, and signs of autonomic nervous system dysfunction (irregular pulse or blood pressure, tachycardia, increased sweating, and cardiac arrhythmias). In addition, increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis), and acute renal failure have occasionally occurred. However, isolated cases of increased creatine kinase and rhabdomyolysis have also been observed, not necessarily associated with NMS. If symptoms of NMS or unexplained fever occur, all neuroleptics, including Aripiprazole, should be discontinued.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extremely severe and associated with ketoacidosis or hyperosmolar coma, including fatal outcomes, has been reported in patients taking atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and a family history of diabetes. In studies of aripiprazole, there were no significant differences in the incidence of hyperglycemic adverse reactions (including diabetes mellitus) or abnormal glucose levels compared to placebo. Based on the available data, it is not possible to make a precise comparative estimate of the incidence of hyperglycemic adverse reactions in patients taking aripiprazole and other atypical antipsychotics. Patients taking any neuroleptics, including aripiprazole, should be closely monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes mellitus should be monitored regularly for elevated glucose levels.

Cardiovascular disorders

The drug should be used with caution in patients with cardiovascular diseases (with ischemic heart disease or previous myocardial infarction, with heart failure and conduction disorders), cerebrovascular diseases and conditions leading to arterial hypotension (dehydration, hypovolemia and taking antihypertensive drugs), arterial hypertension, including progressive or malignant hypertension.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients taking neuroleptics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and all preventive measures should be taken.

QT prolongation.

The incidence of QT prolongation with aripiprazole was comparable to that with placebo. However, caution should be exercised when using aripiprazole in patients with a family history of QT prolongation (see section 4.8).

Epileptic seizures

Seizures have been reported uncommonly with aripiprazole. Therefore, aripiprazole should be used with caution in patients with a history of epilepsy or conditions associated with seizures.

Increased Mortality: Aripiprazole is associated with an increased risk of death in elderly patients with psychosis secondary to Alzheimer's disease. Although the causes of death varied, the majority of deaths were cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature (see Adverse Reactions).

Cerebrovascular adverse reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, have been observed in elderly patients (mean age 84 years; range 78-88 years). A strong dose-response relationship was observed for cerebrovascular adverse reactions in patients taking aripiprazole.

Arilental is not indicated for the treatment of patients with psychosis on the background of dementia.

Hypersensitivity.

When using aripiprazole, hypersensitivity reactions characterized by allergic symptoms may develop (see section "Adverse reactions").

Weight gain.

Patients with schizophrenia and bipolar mania often experience weight gain due to comorbidities, the use of neuroleptics that cause weight gain, and an unhealthy lifestyle; this phenomenon can lead to serious complications. In post-marketing studies, weight gain in patients was observed. When treated with aripiprazole, cases of weight gain were usually observed in patients with significant risk factors, such as a history of diabetes mellitus, thyroid disorders, and the presence of pituitary adenoma.

In studies involving adolescent patients with bipolar mania, weight gain was observed with aripiprazole treatment after 4 weeks of therapy. Weight should be monitored in adolescents with bipolar mania. If weight gain is significant, a dose reduction may be indicated (see section 4.8).

Dysphagia.

Neuroleptics, including aripiprazole, may cause esophageal motility disorders and aspiration of gastric contents. Aripiprazole should be used with caution in patients at increased risk of aspiration pneumonia.

Pathological gambling and other impulse control disorders.

Patients may experience increased episodes of pathological gambling, particularly gambling, and an inability to control these episodes while taking aripiprazole. Hypersexuality, compulsive shopping, binge eating or eating disorders, and other impulsive and compulsive behaviors have also been reported. It is important for physicians to inform patients of the development of new or previously described disorders during treatment with aripiprazole. It should be noted that impulse control symptoms may be related to the underlying disorder; however, resolution of the impulses has occasionally been reported with dose reduction or discontinuation of treatment. Impulse control disorders can be harmful to the patient and others if not recognized. If a patient develops such tendencies while taking aripiprazole, consideration should be given to reducing the dose or discontinuing treatment.

Lactose

The drug contains lactose, therefore patients with rare hereditary disorders such as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients with comorbid ADHD (attention deficit hyperactivity disorder): Despite the high incidence of comorbidity of bipolar I disorder and ADHD, there is very limited safety data on the concomitant use of aripiprazole and stimulants, and extreme caution should be exercised when these agents are co-administered.

Fall

Aripiprazole may cause drowsiness, orthostatic hypotension, motor and sensory instability, which may lead to falls. Caution should be exercised when treating patients at higher risk, and lower starting doses should be considered (e.g., elderly or debilitated patients; see section 4.2).

Use during pregnancy or breastfeeding

Pregnancy

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

Neonates exposed to neuroleptics (including aripiprazole) during the third trimester of pregnancy may experience adverse reactions including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration. There have been reports of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding difficulties. Therefore, close observation of the neonate is necessary.

Breastfeeding period

Aripiprazole is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility.

Aripiprazole does not affect fertility based on data from a reproductive toxicity study.

Ability to influence reaction speed when driving vehicles or other mechanisms

Aripiprazole has minor or moderate influence on the ability to drive and use machines due to potential effects on the nervous system and visual organs and the occurrence of adverse reactions such as sedation, drowsiness, fainting, blurred vision, diplopia (see section "Adverse reactions").

Method of administration and doses

The drug is to be used internally.

Schizophrenia

It is recommended to prescribe Arilental at an initial dose of 10 or 15 mg 1 time per day, regardless of meals. The maintenance dose is 15 mg per day. The drug has been proven effective in doses from 10 to 30 mg per day. Increased effectiveness when taking a daily dose exceeding 15 mg has not been demonstrated, although individual patients may benefit from an increased dose.

The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder: The recommended starting dose of Aricept is 15 mg. This dose should be taken once daily with or without food as monotherapy or as part of combination therapy. In some patients, dose increases may be effective. The maximum daily dose should not exceed 30 mg.

Prevention of recurrence of new manic episodes in bipolar I disorder: To prevent recurrence of manic episodes in patients taking aripiprazole as monotherapy or as part of combination therapy, the drug should be continued at the same dose. The daily dose may be adjusted, including a reduction, based on the clinical condition of the patient.

Special patient groups

Patients with hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. There are insufficient data to make recommendations for patients with severe hepatic impairment. The dose should be titrated with caution in these patients. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2).

Patients with renal impairment: No dose adjustment is required for patients with renal impairment.

Elderly patients: The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in bipolar I disorder in patients aged 65 years and older have not been established. Given the greater sensitivity of this patient population, lower starting doses should be considered when other clinical factors permit (see section 4.4).

Gender: No dose adjustment is required based on the patient's gender (see Pharmacokinetics).

Smoking: Given the metabolic pathway of aripiprazole, no dosage adjustment is required for smokers (see section 4.5).

Dose adjustment due to interactions. When potent CYP3A4 or CYP2D6 inhibitors are co-administered with aripiprazole, the aripiprazole dose should be reduced. If a CYP3A4 or CYP2D6 inhibitor is removed from the combination regimen, the aripiprazole dose should be increased (see section 4.5).

When potent CYP3A4 inducers are co-administered with aripiprazole, the aripiprazole dose should be increased. If the CYP3A4 inducer is removed from the combination regimen, the aripiprazole dose should be reduced to the recommended dose (see section 4.5).

Children

Do not use on children.

Overdose

Symptoms

In adult patients, cases of intentional or accidental acute overdose with aripiprazole at doses up to 1260 mg have been described, which were not fatal. Potentially medically important symptoms observed were lethargy, increased blood pressure, drowsiness, tachycardia, nausea, vomiting and diarrhea.

In addition, there have been reports of accidental overdoses of aripiprazole (up to 195 mg) in children, which were not fatal. Potentially medically significant symptoms observed included drowsiness, transient loss of consciousness, and extrapyramidal symptoms.

In case of overdose, supportive care, airway management, oxygen therapy, mechanical ventilation, and symptom control are necessary. The possibility of multiple drug overdose should be considered. Cardiovascular monitoring should be initiated immediately with ECG monitoring for arrhythmias. After a confirmed or suspected overdose with aripiprazole, close medical observation and monitoring of the patient's condition until recovery is achieved.

Activated charcoal (50 g) administered 1 hour after aripiprazole administration reduced aripiprazole Cmax by approximately 41% and AUC by approximately 51%, indicating the potential efficacy of activated charcoal in the treatment of overdose.

Hemodialysis

Although there are no reliable data on the use of hemodialysis in case of aripiprazole overdose, the beneficial effect of this method is unlikely, because aripiprazole is not excreted unchanged by the kidneys and is extensively bound to plasma proteins.

Adverse reactions

The most common adverse reactions were akathisia and nausea, each occurring in more than 3% of patients taking oral aripiprazole.

All adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 - <1/10), uncommon (≥1/1000 - <1/100), rare (≥1/10000 - <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

The frequency of adverse reactions reported during post-marketing use cannot be estimated as they are derived from spontaneous reports, therefore the frequency of these adverse reactions is classified as unknown.

Temperature regulation disorders (e.g. hypothermia, pyrexia),

chest pain,

peripheral edema

Description of selected adverse reactions

Dystonia

Class effect: Symptoms of dystonia, a prolonged abnormal contraction of muscle groups, may occur in susceptible patients within the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to a tightening of the throat, difficulty swallowing, difficulty breathing, and/or protrusion of the tongue. Although these symptoms may occur at low doses, they occur more frequently and with greater severity at higher doses of first-generation antipsychotics. An increased risk of acute dystonia is observed in males and in younger patients.

Prolactin

In clinical trials for approved indications and in post-marketing surveillance, there were cases of both increases and decreases in serum prolactin compared to baseline.

Laboratory indicators

Elevations in creatine phosphokinase, usually transient and asymptomatic, were observed in 3.5% of patients treated with aripiprazole.

Pathological gambling and other impulse control disorders

Pathological gambling, hypersexuality, compulsive shopping, binge eating, or uncontrolled food cravings may occur in patients taking aripiprazole.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions during post-marketing surveillance. This allows for monitoring of the benefit-risk balance of medicinal products. Healthcare professionals should report suspected adverse reactions.

Expiration date

3 years.

Storage conditions

Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

7 tablets in a blister, 1 blister or 4 blisters in a pack.

Vacation category

According to the recipe.

Producer

Actavis Ltd./Actavis Ltd.

Location of the manufacturer and address of its place of business.

BLB015, BLB016, Bulebel Industrial Estate, m. Zeitoun, ZTN3000, Malta/

BLB015, BLB016, Bulebel Industrial Estate, Zejtun, ZTN3000, Malta.

Applicant.

CJSC "Farmlyga" / UAB "Farmlyga".

Location of the applicant.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.