Ariprizol, tablets 30 mg 30 pcs

Pharmacodynamics

. The therapeutic action of aripiprazole in schizophrenia and type 1 bipolar disorder is presumably due to a combination of partial agonist activity against D2-dopamine and 5HT1a-serotonin receptors and antagonist activity against 5HT2a-serotonin receptors. Aripiprazole in animal experiments showed antagonism to dopaminergic hyperactivity and agonism to dopaminergic hypoactivity. 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, α1-adrenoreceptors and H1-histamine receptors. Aripiprazole is also characterized by moderate affinity for serotonin reuptake sites and no affinity for m-cholinoreceptors. Some of the clinical effects of aripiprazole may be due to interactions with receptors other than dopamine and serotonin receptors.

Aripiprazole oral administration in healthy volunteers at doses of 0.5 to 30 mg once daily for 2 weeks shows a dose-dependent decrease in the binding of 11C-raclopride, a D2/D3-dopamine receptor ligand, to the caudate nucleus and the fence, as measured by positron emission tomography.

Pharmacokinetics

Intake
Aripiprazole is rapidly absorbed after oral administration, with maximum plasma concentration reached after 3-5 hours. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability of the tablets is 87%. High-fat foods have no effect on aripiprazole pharmacokinetics.

Distribution
Aripiprazole is intensely distributed in tissues, the apparent volume of distribution is 4.9 l/kg, indicating significant extravascular distribution. At therapeutic blood concentrations, aripiprazole and its main metabolite dehydroapiprazole are more than 99% bound to plasma proteins, mainly to albumin.

Metabolism
Aripiprazole is metabolized in the liver in three ways: dehydrogenation, hydroxylation and N-dealkylation. According to in vitro studies, dehydrogenation and hydroxylation of aripiprazole occurs under the action of CYP3A4 and CYP2D6 isoenzymes, and N-dealkylation is catalyzed by CYP3A4 isoenzyme. Aripiprazole is the main active ingredient in blood. At equilibrium the area under the concentration-time curve (AUC) of dehydroapiprazole is about 40% of the AUC of aripiprazole in plasma.

Elimination
Mean half-life (T1/2) of aripiprazole is approximately 75 hours in patients with high CYP2D6 isoenzyme activity and approximately 146 hours in patients with low activity of this isoenzyme. Total clearance of aripiprazole is 0.7 mL/min/kg, mainly due to hepatic excretion
After a single oral administration of [14C]-labeled aripiprazole, approximately 27% radioactivity is determined in the urine and approximately 60% in the feces. Less than 1% of unchanged aripiprazole is detected in the urine, and approximately 18% of the ingested dose is excreted unchanged in the feces.

Pharmacokinetics in special patient groups

Pharmacokinetics in children
The pharmacokinetics of aripiprazole and dehydroapiprazole in children from 10 to 17 years was the same as in adults after adjusting for differences in body weight.

Elderly patients
No age-related differences in aripiprazole pharmacokinetic parameters were found in adult patients with schizophrenia and in healthy volunteers.

Gender
No differences in pharmacokinetic parameters of aripiprazole in adult patients with schizophrenia and in age-matched healthy volunteers were found.

Smoking and Race
There were no clinically significant differences in aripiprazole pharmacokinetics based on race and smoking.

Kidney function impairment
Pharmacokinetic parameters of aripiprazole and dehydroapiprazole in patients with severe renal disease do not differ from those in healthy volunteers.

Liver function impairment
After a single dose of aripiprazole by individuals with varying degrees of severity of cirrhosis (Child-Pugh Class A, B, and C), there was no significant effect of hepatic function impairment on the pharmacokinetics of aripiprazole and dehydroariprazole, however, only three patients with decompensated cirrhosis (Child-Pugh Class C) participated in the study, so definitive conclusions cannot be drawn about liver metabolic activity in patients with decompensated cirrhosis.

Indications

Active ingredient

How to take, the dosage

Schizophrenia
The recommended starting dose is 10 mg to 15 mg once daily, regardless of meals. The maintenance dose is 15 mg per day. In clinical trials, the effectiveness of the drug in doses from 10 mg to 30 mg per day has been shown. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar disorder
As monotherapy, the recommended starting dose is 15 mg once daily, regardless of meals. If necessary, the dose should be changed at intervals of at least 24 hours. In clinical trials, the effectiveness of the drug in doses from 15 to 30 mg daily for 3 to 12 weeks has been shown. Safety of the preparation in doses greater than 30 mg daily has not been evaluated in clinical trials.
In observing patients with type I bipolar disorder who have experienced a manic or mixed episode, in whom stabilization of symptoms was observed on aripiprazole for 6 weeks at a dose of 15 mg daily or 30 mg daily at an initial dose of 30 mg daily, followed by 6 months and then for 17 months, favorable effects of such maintenance therapy were established. Patients should be periodically evaluated to determine whether continuation of maintenance therapy is necessary.

Addition to therapy with lithium or valproic acid in bipolar disorder type I
The recommended initial dose is 10 mg to 15 mg once daily, regardless of meals. The maintenance dose is 15 mg per day. The dose can be increased up to 30 mg per day depending on clinical indications.
When observing patients with bipolar disorder type I, a favorable effect of maintenance therapy with aripiprazole at a dose of 10 mg to 30 mg daily as an adjunct to therapy with lithium or valproic acid has been established.
Patients should be evaluated periodically to determine the need for continued maintenance therapy.

Additional therapy for major depressive disorder
The recommended initial dose is 5 mg daily, regardless of meals.
If necessary and well tolerated, the daily dose can be increased weekly by 5 mg up to a maximum of 15 mg per day.
The duration of therapy for all the above indications has not been established. The patient should be regularly monitored for the possibility of withdrawal of therapy.

The use of the drug in special groups of patients

Patients with impaired renal function. There is no need to adjust the dose of the drug.

Patients with hepatic dysfunction.
No dose adjustment is required.
In patients with severe hepatic impairment the dose of 30 mg is prescribed with caution.

Patients aged over 65 years.
No adjustment of the drug dose is required.

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

The effect of smoking on the dosing regimen.
The dosing regimen of the drug is the same for smoking and non-smoking patients.

Dosing regimen in concomitant therapy
In concomitant use of aripiprazole and potent CYP3A4 isoenzyme inhibitors (ketoconazole, clarithromycin) the drug dose should be reduced by half; when CYP3A4 isoenzyme inhibitors are cancelled the drug dose should be increased.

In concomitant use of aripiprazole and potent CYP2D6 isoenzyme inhibitors (quinidine, fluoxetine, paroxetine), the drug dose should be reduced by half; if CYP2D6 isoenzyme inhibitors are cancelled, the drug dose should be increased.
If the drug is prescribed as adjunctive therapy for major depressive disorder, the drug should be used without changing the dosing regimen.

If the drug and potent CYP2D6 isoenzyme inhibitors (quinidine, fluoxetine, paroxetine) and CYP3A4 (ketoconazole, clarithromycin) are used simultaneously, the drug dose should be reduced to 25% of the usual dose. If CYP3A4 and/or CYP2D6 isoenzyme inhibitors are cancelled, the drug dose should be increased.

When concomitant use of the drug and potent, moderate or weak CYP3A4 and CYP2D6 isoenzyme inhibitors, the drug dose may initially be reduced to 25% of the usual dose and then increased to achieve optimal clinical results.

When administering the drug to patients with low CYP2D6 isoenzyme activity, the drug dose should initially be reduced by half and then increased to achieve optimal clinical results. In concomitant use of the drug and a potent CYP3A4 isoenzyme inhibitor in patients with low CYP2D6 isoenzyme activity, the drug dose should be reduced to 25% of the usual dose.

In case of concomitant use of the drug and potential inducers of CYP3A4 isoenzyme (carbamazepine), the drug dose should be doubled. After discontinuation of CYP3A4 isoenzyme inducers, the drug dose should be reduced to the recommended dose.

Interaction

Aripiprazole may increase the effect of antihypertensive drugs because it has an antagonistic effect on alpha1-adrenoreceptors.

The mechanism of action of aripiprazole is related to the effect on the central nervous system; this must be considered when using with other drugs with central action.

Caution should be exercised when using aripiprazole concomitantly with drugs that cause QT interval prolongation or alter electrolyte balance.

The effect of using other drugs on aripiprazole

The H2-histamine receptor blocker famotidine reduces the absorption rate of aripiprazole, but this is not considered to have a clinically significant effect. Aripiprazole is metabolized by various pathways, including participation of CYP2D6 and CYP3A4 isoenzymes, but it is not metabolized by CYP1A isoenzyme, therefore no dose adjustment is required in smoking patients.

Quinidine and other CYP2D6 isoenzyme inhibitors
The results of a clinical study with healthy patients showed that a potent CYP2D6 isoenzyme inhibitor (quinidine) increased AUC of aripiprazole by 107%, while Cmax remained unchanged. AUC and Cmax values of dehydroapiprazole, the active metabolite, were reduced by 32% and 47%, respectively.
The dose of aripiprazole should be reduced by approximately half of the prescribed dose when aripiprazole is concomitantly used with quinidine. Other potent CYP2D6 isoenzyme inhibitors, such as fluoxetine and paroxetine, may have similar effects, so a similar dose reduction of aripiprazole is recommended in case of their concomitant use.

Ketoconazole and other CYP3A4 isoenzyme inhibitors
Results of clinical study with healthy patients showed that strong CYP3A4 isoenzyme inhibitor (ketoconazole) increased aripiprazole AUC and Cmax by 63% and 37%, respectively. AUC and Cmax values of dehydroapiprazole increased by 77% and 43%, respectively.
In slow CYP2D6 isoenzyme metabolizers, concomitant use of potent CYP3A4 isoenzyme inhibitors may lead to high plasma concentrations of aripiprazole compared to fast CYP2D6 isoenzyme metabolizers. When considering the simultaneous use of ketoconazole or other potent CYP3A4 isoenzyme inhibitors with aripiprazole, the possible benefit should exceed the possible risk to the patient.
If ketoconazole and aripiprazole are used concomitantly, the dose of ariprizole® should be reduced by about half the recommended dose.
When aripiprazole is coadministered with other potent CYP3A4 isoenzyme inhibitors, such as itraconazole and HIV protease inhibitors, a similar effect can be expected, so the dose of Ariprizole® should also be reduced.
If a CYP2D6 or CYP3A4 isoenzyme inhibitor is discontinued, the dose of ariprizole® should be increased to a level consistent with that prior to co-administration. When aripiprazole and mild CYP3A4 isoenzyme inhibitors (e.g., diltiazem or escitalopram) or CYP2D6 are used concomitantly, a slight increase in plasma aripiprazole concentration can be expected.

Carbamazepine and other inducers of CYP3A4 isoenzyme
When aripiprazole and carbamazepine, a potent inducer of CYP3A4 isoenzyme were used concomitantly, geometric mean Cmax and AUC of aripiprazole were decreased by 68% and 73%, respectively, and geometric mean Cmax and AUC of dehydroariprazole – by 69% and 71%, respectively, compared to use 30 mg aripiprazole as monotherapy. When co-administered with carbamazepine, the dose of aripiprazole should be doubled. When aripiprazole is coadministered with other potent inducers of CYP3A4 isoenzyme, such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St John’s wort, similar effects may be expected, so the dose of aripiprazole® should be increased. If a CYP3A4 isoenzyme inducer is discontinued, the dose of Ariprizole® should be reduced to the recommended dose.

Drugs of valproic acid and lithium
No significant clinical changes in plasma concentrations of aripiprazole were observed when aripiprazole was used concomitantly with drugs of lithium or valproic acid.

Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole. Signs and symptoms of this condition may appear especially when used with other serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs), or drugs that increase the blood plasma concentration of aripiprazole.

The effect of aripiprazole use on other drugs

. In clinical trials aripiprazole in doses of 10-30 mg/day had no significant effect on metabolism of CYP2D6 (dextromethorphan/3-methoxymorphine), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP3A4 (dextromethorphan) sub-enzymes. In addition, aripiprazole and dehydroapiprazole did not alter the biotransformation of drugs metabolized by CYP1A2 isoenzyme in vitro.

Thus, it is unlikely that aripiprazole can cause clinically significant effects of aripiprazole on drugs metabolized with participation of these isoenzymes. No clinically significant changes in plasma concentrations of valproic acid, lithium or lamotrigine were observed when aripiprazole was used concomitantly with valproic acid, lithium or lamotrigine.

Special Instructions

The therapeutic effect of antipsychotic drugs develops over several days to several weeks. During this period, the patient’s condition should be monitored.

Suicidal attempts.
The phenomena of suicidal behavior are common in psychosis and mood swings, and in some cases they occur immediately after initiation or modification of antipsychotic treatment, including treatment with aripiprazole. Patients at high risk should be monitored when treated with antipsychotics. Results from one epidemiologic study showed that patients with schizophrenia or bipolar disorder did not have an increased risk of suicide when treated with aripiprazole compared with other antipsychotics. There is insufficient clinical data to assess this risk in younger patients (under 18 years of age), but there is evidence to suggest that the risk persists after 4 weeks of treatment with antipsychotics, including aripiprazole.

Cardiovascular disease.
Aripiprazole should be used with caution in patients with cardiovascular disease (myocardial infarction, coronary heart disease, heart failure, cardiac conduction disorders in the history), cerebrovascular disorders, conditions predisposing to arterial hypotension (dehydration, hypovolemia, antihypertensive therapy) or hypertension, including essential or malignant.

In cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Because patients treated with antipsychotics often have acquired risk factors for venous thromboembolism, all possible risk factors for venous thromboembolism should be identified before and during treatment with Ariprizol® with preventive measures.

Conduction disorders.
In clinical trials of aripiprazole, the incidence of QT interval prolongation was comparable to the placebo group. Aripiprazole, like other antipsychotics, should be used with caution in patients with a family history of QT interval prolongation.

Late dyskinesia.
In clinical trials lasting less than 1 year, infrequent cases of dyskinesia requiring urgent treatment have been observed during treatment with aripiprazole. If a patient develops signs and symptoms of tardive dyskinesia during treatment with aripiprazole®, dose reduction or discontinuation of treatment should be considered.

Symptoms of dyskinesia may worsen temporarily or even appear for the first time after discontinuation of therapy.

Other extrapyramidal disorders.
In clinical trials of aripiprazole, akathisia and parkinsonism have been observed in children. If signs and symptoms of other extrapyramidal disorders appear, consideration should be given to reducing the dose of aripiprazole with follow-up monitoring of the patient.

Malignant neuroleptic syndrome (MNS).
Malignant neuroleptic syndrome is a potentially life-threatening set of symptoms associated with the use of antipsychotic drugs. Rare cases of MNS have been observed in clinical studies during treatment with aripiprazole, which is manifested by hyperpyrexia, muscle rigidity, mental disturbances and instability of autonomic nervous system (irregular pulse and blood pressure, tachycardia, sweating, cardiac arrhythmia). In addition, in some cases there are increased CPK activity, myoglobinuria (rhabdomyolysis) and acute renal failure. If symptoms of MNS or unexplained fever occur, all neuroleptics, including Ariprizole®, should be discontinued.

Convulsions.
In clinical studies during treatment with aripiprazole, infrequent occurrence of seizures has been observed. Therefore, aripiprazole should be used with caution in patients with a history of seizures and risk of seizures.

Psychosis associated with senile dementia.
In three placebo-controlled clinical trials of aripiprazole in elderly patients (mean age 82.4 years, age range 56-99 years) with psychosis associated with Alzheimer’s disease, there was an increased risk of mortality compared to the placebo group. The mortality rate with aripiprazole was 3.5 percent compared with 1.7 percent in the placebo group. Although the causes of death varied, the main causes of most deaths were either cardiovascular disorders (including heart failure, sudden death) or the development of infection (including pneumonia).

The same clinical trials in elderly patients (mean age 84 years, age range 78-88 years) reported the development of cerebrovascular adverse reactions (including stroke, transient ischemic attack), including death. Overall, 1.3% of patients treated with aripiprazole had cerebrovascular adverse reactions compared to 0.6% of patients treated with placebo. This difference was not statistically significant. However, one of these fixed-dose aripiprazole studies found a significant dose-response relationship with cerebrovascular adverse reactions.

Aripiprazole® is not recommended for use in patients with psychosis due to dementia.

Hyperglycemia and diabetes mellitus.
Hyperglycemia, occasionally severe and accompanied by ketoacidosis or fatal hyperosmolar coma, has been reported in patients taking atypical neuroleptics. The association between atypical neuroleptics and hyperglycemic disorders remains unclear. In clinical trials of aripiprazole there was no significant difference in the incidence of adverse reactions accompanied by hyperglycemia (including diabetes) or in changes in laboratory glycemic values compared to the placebo group.
Patients diagnosed with diabetes mellitus should have their blood glucose concentrations determined regularly while taking atypical neuroleptics.
Patients with risk factors for diabetes mellitus (obesity, family history of diabetes mellitus) when taking atypical neuroleptics should have their blood glucose determined at the beginning of the course and periodically while taking the drug. In patients taking atypical neuroleptics, continuous monitoring of hyperglycemia symptoms (increased thirst, frequent urination, polyphagia, weakness) is necessary. Special attention should be paid to patients with diabetes mellitus and risk factors for its development.

Hypersensitivity.
As with the use of other drugs, hypersensitivity reactions in the form of allergic symptoms may develop when taking aripiprazole.

Body weight gain.
Increased body weight is commonly seen in patients with schizophrenia and bipolar mania due to the development of comorbidities, use of antipsychotic drugs that cause increased body weight, unhealthy lifestyle that may lead to acute complications. Cases of weight gain have been reported in the post-marketing period in patients taking aripiprazole. Usually these adverse reactions were observed in patients with significant risk factors, such as diabetes mellitus, thyroid disease, or pituitary adenoma. In clinical trials, administration of aripiprazole did not cause a clinically significant increase in body weight.
In clinical studies of adolescent patients with bipolar mania, body weight increased after 4 weeks of treatment while taking aripiprazole. Continuous monitoring of body weight in adolescent patients with bipolar mania is necessary. If increase in body weight is clinically significant, the dose of aripiprazole should be reduced.

Dysphagia.
Cases of disorders of esophageal peristalsis and, as a consequence, aspiration pneumonia have been reported with neuroleptics. The drug should be administered with caution in patients with risk factors for aspiration pneumonia.

Pathological craving for gambling.
During the post-registration period, pathological gambling cravings have been reported in patients taking aripiprazole, regardless of whether these patients have a history of pathological gambling cravings. Patients with a history of pathological gambling cravings may be at increased risk of developing this disorder and should be closely monitored when using aripiprazole.

Lactose.
Aripiprazole® contains lactose, so it is not recommended for patients with rare hereditary conditions associated with galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Patients with concomitant attention deficit hyperactivity disorder (ADHD).
Despite the high frequency of combination of bipolar disorder type I and ADHD, there are very limited data on the safety of concomitant use of aripiprazole and psychostimulants, so caution should be exercised if they are used together.

Influence on driving and operating machinery

As with other neuroleptics, the patient should be advised of the dangers of operating moving machinery and operating a motor vehicle when prescribing aripiprazole.

Contraindications

With caution

. In patients with cardiovascular disease (coronary heart disease or myocardial infarction, heart failure and conduction disorders), cerebrovascular disease and conditions predisposing to arterial hypotension (dehydration, hypovolemia and taking hypotensive drugs) due to the possibility of orthostatic hypotension; in patients with seizures or suffering from diseases that may lead to seizures; in patients with an increased risk of hyperthermia (e.g., with intense physical activity, overheating, taking m-cholinoblockers, dehydration due to the ability of neuroleptics to disrupt thermoregulation); in patients with an increased risk of aspiration pneumonia due to the risk of esophageal motor function failure and aspiration; in patients who are obese and have a family history of diabetes mellitus; in patients at high risk of suicide (psychotic illness, bipolar disorder, major depressive disorder); and in 18-24 year olds because of the risk of suicidal behavior.

Side effects

The following side effects occur more frequently (≥1/100) compared with placebo or are identified as possible clinically significant side effects (*).
The following classification is used to indicate the frequency of side effects: frequent (˃ 1/100 and ˂ 1/10) and infrequent (˃ 1/1000 and ˂ 1/100):

Mental disorders:
often – anxiety, insomnia, anxiety;
infrequently – depression*, increased sexuality.

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

VIight disorders:
often – blurred vision; infrequently – diplopia.

Cardiovascular system disorders:
infrequent – tachycardia*, orthostatic hypotension*.

Gastrointestinal disorders:
often – dyspepsia, vomiting, nausea, constipation, hypersecretion of saliva.

General disorders:
often – fatigue.

Post-marketing surveillance

The following adverse reactions have been reported in post-marketing studies. The frequency of adverse reactions is considered unknown because it cannot be estimated from the available data.

Hematopoietic disorders: leukopenia, neutropenia, thrombocytopenia.

Immune system disorders: allergic reactions (anaphylactic shock, angioedema, including, inflammation of the tongue, tongue swelling, facial edema, itching or urticaria).

Endocrine system disorders: hyperglycemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma.

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

Mental disorders: agitation, nervousness, pathological gambling addiction, suicide attempt, suicidal thoughts, committed suicide.

Nervous system disorders: speech disorder, malignant neuroleptic syndrome, seizures, serotonin syndrome.

Cardiovascular system disorders: prolongation of QT interval, ventricular arrhythmia, sudden death, cardiac arrest, tachycardia, bradycardia, syncope, increased blood pressure, thromboembolism (including pulmonary embolism and deep vein thrombosis).

Respiratory system: oropharyngeal spasm, laryngospasm, aspiration pneumonia.

Gastrointestinal tract: pancreatitis, dysphagia, abdominal heaviness, diarrhea.

Hepatic and biliary tract disorders: liver failure, jaundice, hepatitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity.

Skin and subcutaneous tissue: rash, photosensitivity, alopecia, hyperhidrosis.

Muscular system disorders: rhabdomyolysis, myaglia, muscle weakness.

Urinary system disorders: urinary incontinence, urinary retention.

Reproductive system disorders: priapism.

General disorders: disorders of temperature regulation (including hypothermia, pyrexia), chest pain, peripheral edema, increased creatine phosphokinase (CPK) activity, increased blood glucose levels, blood glucose fluctuations, increased glycohemoglobin levels.

Overdose

In clinical trials there have been cases of accidental or intentional overdose of aripiprazole with a single dose of up to 1260 mg that were not fatal.

Symptoms:lethargy, increased blood pressure, drowsiness, tachycardia, loss of consciousness, nausea, vomiting, diarrhea. No clinically significant changes in basic physiological parameters, laboratory parameters and ECG were found in hospitalized patients.

There have been cases of aripiprazole overdose in children (taken up to 195 mg) without fatal outcome.Potentially dangerous symptoms of overdose are somnolence, extrapyramidal disorders and transient loss of consciousness.

Treatment: monitoring of vital functions, ECG to detect possible arrhythmias, supportive therapy, ensuring airway patency, oxygenation, effective ventilation, activated charcoal, symptomatic treatment, close medical observation until all symptoms disappear. There are no data on the use of hemodialysis in aripiprazole overdose; a favorable effect of this method is unlikely, since aripiprazole is not excreted unchanged by the kidneys and is largely bound to plasma proteins.

Similarities