Aripiprazole®

INSTRUCTIONS for medical use of the medicinal product Ariprazol® (Ariprazol)

Composition:
Active substance: aripiprazole;
1 tablet contains aripiprazole 10 mg or 15 mg (calculated as 100% dry substance aripiprazole).
Excipients: hydroxypropylmethylcellulose; sodium croscarmellose; lactose monohydrate; microcrystalline cellulose; citric acid monohydrate; colloidal anhydrous silicon dioxide; magnesium stearate.

Dosage form:
Tablets.

Main physicochemical properties:
Tablets 10 mg: white or almost white tablets, flat surface, round shape with bevel, with a score line on one side;
Tablets 15 mg: white or almost white tablets, flat surface, round shape with bevel, with marking "15" on one side.

Pharmacotherapeutic group:
Psychotropic agents. Other antipsychotic agents.
ATC code: N05AX12.

Pharmacological properties

Pharmacodynamics
Mechanism of action
The efficacy of aripiprazole in schizophrenia and bipolar I disorder is thought to be mediated by its partial agonism at dopamine D2 and serotonin 5-HT1A receptors, and antagonism at serotonin 5-HT2A receptors. Aripiprazole has been shown in animal models to exhibit antagonistic properties in conditions of dopamine hyperactivity and agonistic properties in conditions of dopamine hypoactivity. Aripiprazole has high in vitro affinity for dopamine D2 and D3 receptors, serotonin 5-HT1A and 5-HT2A receptors, and moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic, and histamine H1 receptors. Aripiprazole also has moderate affinity for serotonin receptors and lacks significant affinity for muscarinic receptors. Interactions with other receptors, besides the above-mentioned dopamine and serotonin receptor subtypes, may explain some of the other clinical effects of aripiprazole.

When administered once daily for two weeks to healthy volunteers at doses ranging from 0.5 to 30 mg, aripiprazole dose-dependently reduced the binding of 11C-raclopride, a D2/D3 dopamine receptor ligand, to the caudate nucleus and putamen, as determined by positron emission tomography.

Clinical efficacy and safety

Adults

Schizophrenia
In three short-term (4 to 6 weeks) placebo-controlled studies involving 1228 adult patients with schizophrenia with positive and negative symptoms, aripiprazole demonstrated statistically significant improvement in psychiatric symptoms compared to placebo. Aripiprazole is effective in maintaining clinical improvement during continued therapy in adult patients who showed an initial response to treatment. In a controlled study using haloperidol as the control drug, the number of patients who responded to therapy and continued to respond at week 52 was similar in both groups (77% in the aripiprazole group and 73% in the haloperidol group). The overall study discontinuation rate was significantly higher in patients taking aripiprazole (43%) compared to those taking haloperidol (30%). Actual scores on assessment scales, including PANSS (Positive and Negative Syndrome Scale) and Montgomery-Åsberg Depression Rating Scale, used as secondary endpoints, demonstrated significant improvement compared to haloperidol. In a 26-week placebo-controlled study in patients with stabilized chronic schizophrenia, aripiprazole significantly reduced the rate of relapse: 34% in the aripiprazole group and 57% in the placebo group.

Weight gain
Clinical studies did not reveal clinically significant weight gain associated with aripiprazole use. In a 26-week controlled (active comparator olanzapine), double-blind, multinational schizophrenia study involving 314 patients, using weight gain as the primary endpoint, significantly fewer patients gained at least 7% of their baseline weight (i.e., at least 5.6 kg with a mean baseline body weight of 80.5 kg) with aripiprazole (N = 18, or 13% of evaluable patients) compared to olanzapine (N = 45, or 33% of evaluable patients).

Lipid parameters
In a combined analysis of lipid parameters from placebo-controlled clinical studies in adult patients, no clinically significant changes in total cholesterol, triglycerides, high-density lipoprotein (HDL), or low-density lipoprotein (LDL) concentrations induced by aripiprazole were observed.

Prolactin
Prolactin levels were measured in all studies across all aripiprazole doses (n = 28242). The incidence of hyperprolactinemia or elevated serum prolactin levels in patients receiving aripiprazole (0.3%) was similar to that observed in the placebo group (0.2%). In patients receiving aripiprazole, the median time to onset of such changes was 42 days, and the median duration was 34 days. The incidence of hypoprolactinemia or decreased serum prolactin levels in patients receiving aripiprazole was 0.4%, compared to 0.02% in the placebo group. In patients receiving aripiprazole, the median time to onset of such changes was 30 days, and the median duration was 194 days.

Manic episodes in bipolar I disorder
In two 3-week placebo-controlled monotherapy dose-adjustment studies involving patients with manic or mixed episodes of bipolar I disorder, aripiprazole demonstrated higher efficacy compared to placebo. Efficacy was determined by reduction in severity of manic symptoms over 3 weeks of treatment. These studies included patients with and without psychotic symptoms, and with and without rapid cycling. In one 3-week placebo-controlled monotherapy study with fixed doses in patients with manic or mixed episodes of bipolar I disorder, aripiprazole did not demonstrate greater efficacy compared to placebo. In two 12-week monotherapy studies (one placebo-controlled and one active comparator) involving patients with manic or mixed episodes of bipolar I disorder with or without psychotic symptoms, aripiprazole demonstrated higher efficacy by week 3 and sustained effect comparable to lithium or haloperidol by week 12. The number of patients with mania in whom aripiprazole induced symptom remission was comparable to the number of patients receiving lithium or haloperidol by week 12.

In a 6-week placebo-controlled study involving patients with manic or mixed episodes of bipolar I disorder with or without psychotic symptoms, initial 2-week monotherapy with lithium or valproate at therapeutic doses was partially ineffective. However, adding aripiprazole as adjunctive therapy resulted in effective reduction of manic symptoms compared to monotherapy with lithium or valproate.

In a 26-week placebo-controlled study with a 74-week extension, patients with manic disorder who achieved remission during the stabilization phase with aripiprazole were randomized. In this study, aripiprazole was more effective than placebo in preventing relapse of bipolar disorder (mainly mania), but did not differ from placebo in preventing depressive relapse.

In a 52-week placebo-controlled study of patients with manic or mixed episodes of bipolar I disorder who were in prolonged remission (total score on Young Mania Rating Scale (Y-MRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) ≤ 12), adding aripiprazole (10 mg/day and 30 mg/day) to lithium or valproate for 12 weeks resulted in better outcomes compared to adding aripiprazole to placebo, reducing the risk of relapse of bipolar episodes by 46% (relative risk RR) and reducing the risk of relapse of manic episodes by 65% (RR = 0.35). However, this combination did not surpass placebo effect in preventing depressive relapse. Adding aripiprazole was superior to placebo on the secondary endpoint of Clinical Global Impression-Bipolar Disorder (CGI-BP) severity score.

In this open-label study, patients were divided into groups receiving monotherapy with lithium or valproate to identify patients with partial response to therapy. Patients were stabilized for at least 12 weeks by adding aripiprazole to the same mood stabilizers. Stabilized patients were randomized to continue therapy with the same mood stabilizers plus aripiprazole or placebo using a double-blind method. Four subgroups participated in the randomized phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The rate of relapse of any mood change, determined by Kaplan-Meier method, was: 16% in the aripiprazole + lithium group and 18% in the aripiprazole + valproate group, compared to 45% in the placebo + lithium group and 19% in the placebo + valproate group.

Pharmacokinetics

Absorption
Aripiprazole is well absorbed, with maximum plasma concentration (Cmax) reached within 3-5 hours after administration. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability of the drug after oral administration is 87%. Consumption of a high-fat meal does not affect the pharmacokinetics of aripiprazole.

Distribution
Aripiprazole is widely distributed in body tissues. The volume of distribution is 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic doses, aripiprazole and dehydroaripiprazole are more than 99% bound to plasma proteins, primarily to albumin.

Biotransformation
Aripiprazole is extensively metabolized in the liver, primarily via dehydrogenation, hydroxylation, and N-dealkylation. According to in vitro data, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the main substance of the drug present in systemic circulation. At steady state, dehydroaripiprazole, its active metabolite, accounts for approximately 40% of the area under the plasma concentration-time curve (AUC) of aripiprazole.

Elimination
The mean elimination half-life of aripiprazole is approximately 75 hours in individuals with normal CYP2D6 metabolism and approximately 146 hours in poor CYP2D6 metabolizers. The total clearance of aripiprazole is 0.7 mL/min/kg, primarily due to hepatic clearance. After a single oral dose of 14C-labeled aripiprazole, approximately 27% was excreted in urine and approximately 60% in feces. Less than 1% of unchanged aripiprazole was excreted in urine, and approximately 18% of unchanged aripiprazole was excreted in feces.

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 is also no significant effect of age in the population pharmacokinetic analysis in patients with schizophrenia.

Sex
There are no differences in the pharmacokinetics of aripiprazole between healthy men and women, and no significant effect of sex in the population pharmacokinetic analysis in patients with schizophrenia.

Smoking
Population pharmacokinetic assessment did not reveal a clinically significant effect of smoking on the pharmacokinetics of aripiprazole.

Race
Population pharmacokinetic assessment did not reveal a clinically significant effect of ethnic differences on the pharmacokinetics of aripiprazole.

Renal impairment
Pharmacokinetic characteristics of aripiprazole and dehydroaripiprazole were found to be similar in patients with severe renal disease and in young healthy volunteers.

Hepatic impairment
In a single-dose study in patients with varying degrees of liver cirrhosis (Child-Pugh classes A, B, and C), no significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydroaripiprazole was observed. However, only three patients with Child-Pugh class C cirrhosis were included in the study, which is insufficient to draw conclusions about metabolic capacity.

Clinical characteristics

Indications
Ariprazol® is indicated for the treatment of schizophrenia in adults. Ariprazol® is also indicated for the treatment of moderate to severe manic episodes in bipolar I disorder and for the prevention of new manic episodes in adults who have previously experienced manic episodes and responded to aripiprazole treatment.

Contraindications
Hypersensitivity to aripiprazole or to any other component of the drug.

Interaction with other medicinal products and other forms of interaction
Due to antagonism at α1-adrenergic receptors, aripiprazole may potentiate the effect of some antihypertensive drugs. Because of the primary effect of aripiprazole on the central nervous system (CNS), caution should be exercised when prescribing aripiprazole with alcohol and other CNS-acting drugs due to possible cross side effects such as sedative effects (see section "Special precautions for use"). Aripiprazole should be used with caution together with other drugs that prolong the QT interval or disrupt electrolyte balance.

Potential effect of other medicinal products on aripiprazole

Hydrochloric acid secretion inhibitor, H2-histamine receptor antagonist famotidine reduces the absorption rate of aripiprazole, but this effect is not considered clinically significant.

Aripiprazole is metabolized by several pathways involving CYP2D6 and CYP3A4 enzymes, but not CYP1A enzymes. Thus, smokers do not require dose adjustment.

Quinidine and other CYP2D6 inhibitors
In a clinical study in healthy volunteers, a potent CYP2D6 enzyme inhibitor (quinidine) increased the AUC of aripiprazole by 107%, while Cmax remained unchanged. The AUC and Cmax values of dehydroaripiprazole, the active metabolite of aripiprazole, decreased by 32% and 47%, respectively. The dose of aripiprazole should be reduced by approximately half when co-administered with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have a similar effect, so dose reduction should be similar when used.

Ketoconazole and other CYP3A4 inhibitors
In a clinical study in healthy volunteers, a potent CYP3A4 enzyme inhibitor (ketoconazole) increased the AUC and Cmax of aripiprazole by 63% and 37%, respectively. The AUC and Cmax values of dehydroaripiprazole increased by 77% and 43%, respectively. In individuals with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may lead to higher plasma concentrations of aripiprazole compared to individuals with normal CYP2D6 metabolism. If co-administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefit should outweigh the possible risk to the patient. When co-administering aripiprazole with ketoconazole, the dose of aripiprazole should be reduced by approximately half. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, may theoretically have similar effects, so doses should be similarly reduced (see section "Dosage and administration"). After discontinuation of a CYP2D6 or CYP3A4 inhibitor, the dose of aripiprazole should be increased to the level used before starting concomitant therapy.

A slight increase in aripiprazole concentration may occur with concomitant use of weak CYP3A4 inhibitors (diltiazem) or CYP2D6 inhibitors (escitalopram).

Carbamazepine and other CYP3A4 inducers
After co-administration of carbamazepine, a potent CYP3A4 inducer, with aripiprazole in patients with schizophrenia or schizoaffective disorder, the mean geometric values of Cmax and AUC of aripiprazole decreased by 68% and 73%, respectively, compared to monotherapy with aripiprazole (30 mg). Similarly, when carbamazepine was co-administered with dehydroaripiprazole, the mean geometric values of Cmax and AUC of the latter decreased by 69% and 71%, respectively, compared to aripiprazole monotherapy. The dose of aripiprazole should be doubled when co-administered with carbamazepine. Concomitant use of aripiprazole with other potent CYP3A4 inducers (rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John's wort), which theoretically have a similar effect to the above-mentioned potent CYP3A4 inhibitors, requires appropriate dose increase. 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 concentration were observed when valproate or lithium were co-administered with aripiprazole, so dose adjustment is not required when using valproate or lithium with aripiprazole.

Serotonin syndrome
Cases of serotonin syndrome have been observed in patients taking aripiprazole, especially when co-administered with other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine reuptake inhibitors (SNRIs), or drugs that increase aripiprazole concentration (see section "Special precautions for use").

Potential effect of aripiprazole on other medicinal products
In clinical studies, aripiprazole at doses of 10-30 mg/day did not affect the metabolism of CYP2D6 substrates (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A. Additionally, in vitro studies did not reveal the ability of aripiprazole and dehydroaripiprazole to affect metabolic pathways mediated by CYP1A2 enzyme. Thus, it is unlikely that aripiprazole can cause clinically significant drug interactions mediated by these enzymes. No clinically significant changes in valproate, lithium, or lamotrigine concentrations were observed when aripiprazole was co-administered with valproates, lithium, or lamotrigine.

Special precautions for use
When treating with antipsychotic drugs, clinical improvement in the patient may take from several days to several weeks. During this period, careful monitoring of the patient's condition is required.

Suicidal tendencies
Suicidal behavior is characteristic of patients with psychotic disorders and affective disorders and has been observed shortly after initiation or change in antipsychotic treatment, including treatment with aripiprazole. Antipsychotic treatment should be accompanied by careful monitoring of patients at high risk.

Cardiovascular disorders
Aripiprazole should be used with caution in patients with a history of cardiovascular diseases (myocardial infarction or ischemic heart disease, heart failure or conduction disorders), cerebrovascular disorders, conditions predisposing patients to hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or hypertension, including progressive or malignant hypertension. Cases of venous thromboembolism (VTE) have been observed during antipsychotic treatment. Since patients taking antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during aripiprazole treatment, and all preventive measures should be taken.

Prolongation of QT interval
In clinical studies of aripiprazole, the frequency of QT interval prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT interval prolongation (see section "Side effects").

Tardive dyskinesia
During clinical studies lasting one year or less, reports of dyskinesia with aripiprazole were infrequent. If symptoms of tardive dyskinesia occur in a patient taking aripiprazole, consideration should be given to reducing the dose or discontinuing treatment. These symptoms may temporarily worsen or even appear after discontinuation of treatment.

Other extrapyramidal symptoms
Akathisia and parkinsonism were observed with aripiprazole use in children. If signs of other extrapyramidal symptoms occur, dose reduction should be considered and careful clinical monitoring of the patient's condition should be conducted.

Neuroleptic malignant syndrome (NMS)
NMS is a complex of symptoms associated with the use of antipsychotic drugs, which can potentially be fatal. NMS was rarely observed in clinical studies of aripiprazole. Clinical manifestations of NMS include hyperpyrexia (very high body temperature), muscle rigidity, altered mental status, and signs of autonomic nervous system dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and cardiac arrhythmia). Additional signs may include elevated creatine kinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. However, isolated cases of elevated creatine kinase levels and rhabdomyolysis, not necessarily associated with NMS, have been observed. If a patient develops symptoms of NMS or unexplained very high body temperature without additional clinical manifestations of NMS, all neuroleptic drugs, including aripiprazole, should be discontinued.

Seizures
Rare cases of seizures have been observed during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients with a history of epilepsy or conditions associated with seizures.

Elderly patients with psychosis associated with dementia

Increased mortality
In three placebo-controlled studies (n = 938; mean age: 82.4 years; range: 56 to 99 years) in elderly patients with psychosis associated with Alzheimer's disease, the risk of fatal outcome was increased with aripiprazole compared to placebo. The mortality rate in patients receiving aripiprazole was 3.5% compared to 1.7% in the placebo group. Although the causes of fatal outcomes were varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) nature.

Cerebrovascular adverse reactions
In the same clinical studies, cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal outcomes (mean patient age was 84 years, age range 78-88 years), were reported. Overall, in these studies, cerebrovascular adverse reactions developed in 1.3% of patients taking aripiprazole compared to 0.6% of patients in the placebo group. This difference was not statistically significant. However, in one of these studies (fixed-dose study), a pronounced dose-dependent relationship between aripiprazole and the occurrence of cerebrovascular adverse reactions was observed in patients taking aripiprazole. Aripiprazole is not indicated for the treatment of psychosis associated with dementia.

Hyperglycemia and diabetes mellitus
Hyperglycemia, in some cases extremely severe and associated with ketoacidosis or hyperosmolar coma, including fatal outcomes, has been observed in patients taking atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and family history of diabetes. In clinical studies of aripiprazole, no significant differences in the frequency of adverse reactions associated with hyperglycemia (including diabetes mellitus) or abnormal laboratory glucose parameters were observed compared to placebo. There is no precise comparative assessment of the risks of adverse reactions associated with hyperglycemia in patients taking aripiprazole and other atypical antipsychotics. Careful monitoring of patients taking any antipsychotics, including aripiprazole, is required, recording symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, and weakness), and regular monitoring of glucose levels in patients with diabetes or risk factors for diabetes development is necessary.

Hypersensitivity
As with other medicinal products, hypersensitivity reactions, manifesting as allergy symptoms, may develop with aripiprazole use.

Weight gain
Patients with schizophrenia and bipolar mania often experience weight gain due to comorbid conditions, use of antipsychotics known to cause weight gain, and negative impact on healthy lifestyle, which can lead to serious complications. During treatment with aripiprazole, weight gain was usually observed in patients with serious risk factors, such as diabetes, thyroid disorders, or pituitary adenoma in history. In clinical studies, no clinically significant weight gain in adults due to aripiprazole use was observed. In clinical studies in adolescent patients with bipolar mania, aripiprazole use for 4 weeks was associated with weight gain. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain becomes clinically significant, consideration should be given to reducing the dose of the drug (see section "Side effects").

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

Pathological gambling and other impulse control disorders
Cases of pathological gambling and inability to control this tendency have been reported in patients prescribed aripiprazole. Hypersexuality, uncontrollable urge to shop, overeating or uncontrolled food craving, and other disorders of impulsive and compulsive behavior have also been reported. It is important that patients and caregivers inform the doctor about the development of new or the above-mentioned disorders during treatment with aripiprazole. Impulse control disorder symptoms may be related to the underlying disorder, but sometimes pathological tendencies have been reported to disappear with dose reduction or discontinuation of treatment. Impulse control disorders can harm the patient and others if not detected. If such disorders develop during aripiprazole use, consideration should be given to reducing the dose or discontinuing treatment.

Lactose
Ariprazol® tablets contain lactose. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Patients with comorbid ADHD (attention deficit hyperactivity disorder)
Despite the high frequency of comorbid bipolar I disorder and ADHD, there are very limited safety data on the concomitant use of aripiprazole and stimulants, so extreme caution is required when prescribing these agents together.

Falls
Aripiprazole may cause drowsiness, orthostatic hypotension, motor and sensory instability, which may lead to falls. Caution should be exercised when treating patients at increased risk, and treatment should be initiated with lower starting doses (e.g., for elderly or debilitated patients).

Use during pregnancy or breastfeeding

Pregnancy
Adequate controlled studies of aripiprazole in pregnant women have not been conducted. Congenital anomalies have been reported, but a causal relationship with aripiprazole has not been established. Animal study data do not allow exclusion of possible embryofetotoxicity. Patients should inform their doctor about pregnancy or intention to become pregnant during aripiprazole treatment. Due to insufficient information on the safety of aripiprazole use in humans and ambiguity of animal study results, the drug may be prescribed during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus. In newborns whose mothers took neuroleptics (including aripiprazole) during the third trimester of pregnancy, adverse reactions may occur, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration. Cases of agitation, increased or decreased muscle tone, tremor, drowsiness, respiratory disorders, or feeding problems have been reported. Therefore, careful monitoring of such newborns is required.

Breastfeeding period
Aripiprazole/metabolites are excreted in breast milk. When deciding on discontinuation of breastfeeding or discontinuation/cessation of aripiprazole use, the benefit of breastfeeding for the child and the benefit of therapy for the mother should be evaluated.

Fertility
It is known from reproductive toxicity studies that aripiprazole does not have a negative effect on fertility.

Ability to affect reaction speed when driving or operating machinery
Aripiprazole, like other neuroleptics, has a moderate or minor effect on the ability to drive due to nervous system and visual organ side effects, such as sedative effect, drowsiness, syncope, blurred vision, diplopia (see section "Side effects").

Dosage and administration
Route of administration: Ariprazol® is intended for oral use.

Adults

Schizophrenia
The recommended initial dose of Ariprazol® is 10 or 15 mg/day, and the maintenance dose is 15 mg/day. This dose is taken once daily, regardless of food intake. Ariprazol® is effective in the dose range of 10 to 30 mg/day. Increased efficacy with doses exceeding 15 mg/day has not been demonstrated, although higher doses may be beneficial for individual patients. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder
The recommended initial dose of Ariprazol® is 15 mg. This dose is taken once daily, regardless of food intake. The drug can be prescribed as monotherapy or as part of combination therapy. For some patients, dose increase may be effective. The maximum daily dose should not exceed 30 mg.

Prevention of new manic episodes in bipolar I disorder
To prevent relapses of manic episodes in patients who received aripiprazole as monotherapy or as part of combination therapy, the drug should be continued at the same dose. Based on the patient's clinical condition, daily dose adjustment, including dose reduction, may be possible.

Patients with hepatic impairment
Patients with mild or moderate hepatic insufficiency do not require dose adjustment. There are insufficient data to provide recommendations for patients with severe hepatic function impairment. Doses in these patients should be carefully selected. For patients with severe hepatic function impairment, the maximum daily dose of 30 mg should be used with caution.

Patients with renal impairment
Patients with renal impairment do not require dose adjustment.

Elderly patients
The efficacy and safety of Ariprazol® in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older have not been established. Considering the higher sensitivity of this patient population, the possibility of using lower initial doses should be considered if other clinical factors allow.

Sex
Dose adjustment based on patient sex is not required.

Smoking
Due to the metabolism pathway of aripiprazole, smokers do not require dose adjustment.

Dose adjustment due to interactions
When co-administering potent CYP3A4 or CYP2D6 inhibitors with aripiprazole, the dose of aripiprazole should be reduced. When a CYP3A4 or CYP2D6 inhibitor is discontinued from combination therapy, the dose of aripiprazole should be increased. When co-administering potent CYP3A4 inducers with aripiprazole, the dose of aripiprazole should be increased. When a CYP3A4 inducer is discontinued from combination therapy, the dose of aripiprazole should be reduced to the recommended dose.

Children
Ariprazol® at this dosage is not recommended for use in children.

Overdose

Signs and symptoms
During clinical studies and based on post-marketing experience in adult patients, cases of intentional or accidental acute overdose of aripiprazole with doses up to 1260 mg without fatal outcome have been observed. Potentially medically significant signs and symptoms observed were lethargy, increased blood pressure, drowsiness, tachycardia, nausea, vomiting, and diarrhea. Additionally, data on accidental overdose with aripiprazole alone (up to 195 mg) in children without fatal outcomes have been obtained. Potentially medically significant symptoms observed were drowsiness, brief loss of consciousness, and extrapyramidal symptoms.

Treatment
Treatment of overdose should include supportive therapy, ensuring airway patency, oxygen therapy, artificial ventilation, and symptom control. The possibility of overdose with multiple medicinal products should be considered. Therefore, immediate monitoring of cardiovascular status is required, including continuous ECG monitoring to detect possible arrhythmias. After confirmed or probable aripiprazole overdose, careful medical monitoring and patient status control are required until recovery. Activated charcoal (50 g), administered 1 hour after aripiprazole intake, reduced the Cmax of aripiprazole by approximately 41% and the AUC by approximately 51%, indicating possible effectiveness of activated charcoal in overdose treatment. Hemodialysis Although information on the effect of hemodialysis on aripiprazole overdose treatment is lacking, hemodialysis is unlikely to be beneficial in overdose treatment due to the extensive plasma protein binding of aripiprazole.

Side effects

Brief description of safety profile
The most common side effects reported in placebo-controlled studies were akathisia and nausea, each occurring in more than 3% of patients receiving oral aripiprazole.

The frequency of occurrence of side effects (SE) associated with aripiprazole therapy, based on adverse effects reported during clinical trials and/or post-marketing use, is listed below. The frequency of side effects is defined by the following criteria: very common (≥ 1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (frequency cannot be determined from available data). Within each group, side effects are listed in order of decreasing severity.

The frequency of side effects reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Therefore, the frequency of these adverse events is classified as "not known."

Metabolism and nutrition disorders:
Common – diabetes mellitus; uncommon – hyperglycemia; frequency not known – hyponatremia, anorexia.

Blood and lymphatic system disorders:
Frequency not known – leukopenia, neutropenia, thrombocytopenia.

Immune system disorders:
Frequency not known – allergic reactions (e.g., anaphylactic reactions, angioedema, tongue swelling, facial swelling, pruritus, or urticaria).

Endocrine system disorders:
Uncommon – hyperprolactinemia, decreased blood prolactin levels; frequency not known – diabetic ketoacidosis, diabetic hyperosmolar coma.

Psychiatric disorders:
Common – anxiety, insomnia, restlessness; uncommon – depression, hypersexuality; frequency not known – agitation, nervousness, pathological gambling, aggression, suicide attempts, suicidal ideation and suicide, impulse control disorders, overeating, compulsive buying, pyromania.

Nervous system disorders:
Common – extrapyramidal disorders, akathisia, tremor, dizziness, somnolence, sedative effect, headache; uncommon – tardive dyskinesia, dystonia, restless legs syndrome; frequency not known – speech disorders, neuroleptic malignant syndrome (NMS), grand mal seizure, serotonin syndrome.

Eye disorders:
Common – blurred vision; uncommon – diplopia, photophobia; frequency not known – oculogyric crisis.

Cardiac disorders:
Uncommon – tachycardia; frequency not known – ventricular arrhythmia, sudden death, cardiac arrest, torsades de pointes ventricular tachycardia, bradycardia.

Vascular disorders:
Uncommon – orthostatic hypotension; frequency not known – syncope/fainting, hypertension, venous thromboembolism (including pulmonary embolism and deep vein thrombosis).

Respiratory, thoracic and mediastinal disorders:
Uncommon – hiccups; frequency not known – oropharyngeal spasm, laryngospasm, aspiration pneumonia.

Gastrointestinal disorders:
Common – dyspepsia, vomiting, nausea, constipation, excessive salivation; frequency not known – pancreatitis, dysphagia, gastrointestinal discomfort, diarrhea.

Hepatobiliary disorders:
Frequency not known – liver failure, jaundice, hepatitis.

Skin and subcutaneous tissue disorders:
Frequency not known – rash, photosensitivity reactions, alopecia, increased sweating, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders:
Frequency not known – rhabdomyolysis, myalgia, muscle rigidity.

Renal and urinary disorders:
Frequency not known – urinary incontinence, urinary retention.

Pregnancy, postpartum and perinatal conditions:
Frequency not known – drug withdrawal syndrome in newborns.

Reproductive system and breast disorders:
Frequency not known – priapism.

General disorders:
Common – fatigue; frequency not known – temperature regulation disorders (e.g., hypothermia, hyperthermia), chest pain, peripheral edema.

Laboratory and instrumental test results:
Frequency not known – weight loss, weight gain, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased gamma-glutamyl transferase (GGT) levels, increased alkaline phosphatase levels; QT interval prolongation, increased creatine phosphokinase (CPK) levels, increased blood glucose levels, blood glucose fluctuations, increased glycated hemoglobin levels.

Description of individual side effects

Adults

Extrapyramidal symptoms (EPS)
Schizophrenia
In a 52-week controlled study in patients receiving aripiprazole, the incidence of EPS, including parkinsonism, akathisia, dystonia, and dyskinesia, was lower (25.7%) compared to patients receiving haloperidol (57.3%). In a long-term 26-week placebo-controlled study, the incidence of EPS was 19% for patients treated with aripiprazole and 13.1% for patients receiving placebo. In another 26-week controlled study, the incidence of EPS was 14.8% for patients receiving aripiprazole treatment and 15.1% for patients receiving olanzapine treatment.

Manic episodes in bipolar I disorder
In a controlled 12-week study, the incidence of EPS was 23.5% for patients treated with aripiprazole and 53.3% for patients receiving haloperidol. In another 12-week study, the incidence of EPS was 26.6% for patients receiving aripiprazole and 17.6% for patients receiving lithium. In the long-term 26-week placebo-controlled study phase, the incidence of EPS was 18.2% for patients receiving aripiprazole and 15.7% for patients receiving placebo.

Akathisia
In placebo-controlled studies, the incidence of akathisia in patients with bipolar disorder was 12.1% with aripiprazole treatment and 3.2% in the placebo group. In patients with schizophrenia, the incidence of akathisia was 6.2% with aripiprazole use and 3.0% in the placebo group.

Dystonia
Class effect of medicinal products: symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible patients during the first few days of treatment. Dystonia symptoms include neck muscle spasms, sometimes progressing to throat tension, difficulty swallowing, difficulty breathing, and/or tongue protrusion. Although these symptoms may occur at low doses, they occur more frequently and with greater severity at higher doses of first-generation antipsychotic drugs. The risk of acute dystonia is higher in men and younger patients.

Prolactin
In clinical trials for approved indications and during the post-marketing period, both increases and decreases in serum prolactin levels compared to baseline levels have been observed.

Laboratory parameters
Comparison of laboratory parameters (including lipid profile) in patients receiving aripiprazole and placebo did not reveal potentially clinically significant differences. Increased CPK levels (mostly transient and asymptomatic) were observed in 3.5% of patients taking aripiprazole, compared to 2.0% in the placebo group.

Pediatric patients

Schizophrenia in adolescents aged 15 years
In a short-term placebo-controlled clinical study involving 302 adolescents (aged 13 to 17 years) with schizophrenia, the frequency and type of side effects were similar to those in adults, except for the following reactions, which were more frequently reported in adolescents receiving aripiprazole than in adults receiving aripiprazole (more frequently than placebo):
These include somnolence/sedative effect and extrapyramidal disorders (very common), as well as dry mouth, increased appetite, orthostatic hypotension (common). The safety profile determined in a 26-week open-label study was similar to the safety profile determined in the short-term placebo-controlled study. The safety profile determined in a long-term double-blind placebo-controlled clinical study was also similar, except for the following side effects, which were common and more frequently observed in children and adolescents compared to the placebo group: weight loss, increased blood insulin levels, arrhythmia, and leukopenia. In the combined group of adolescents with schizophrenia aged 13-17 years with drug exposure duration up to 2 years, the frequency of decreased prolactin levels in girls (<3 ng/mL) and boys (<2 ng/mL) was 29.5% and 48.3%, respectively. In adolescents with schizophrenia aged 13-17 years receiving 5 to 30 mg aripiprazole for up to 72 months, the frequency of decreased prolactin levels in girls (<3 ng/mL) and boys (<2 ng/mL) was 25.6% and 45.0%, respectively. In two clinical studies involving adolescents (aged 13-17 years) with schizophrenia and bipolar disorder receiving aripiprazole, the frequency of decreased prolactin levels in girls (<3 ng/mL) and boys (<2 ng/mL) was 37.0% and 59.4%, respectively.

Manic episodes in bipolar I disorder in adolescents aged 13 years
The frequency and type of side effects in adolescents with bipolar I disorder were similar to those in adults, except for the following side effects:
Very common (≥ 1/10) – somnolence (23.0%), extrapyramidal disorders (18.4%), akathisia (16.0%), and fatigue (11.8%);
Common (≥ 1/100, <1/10) – upper abdominal pain, increased heart rate, weight gain, increased appetite, muscle twitching, and dyskinesia.
The following side effects may be dose-dependent: extrapyramidal disorders (incidence with aripiprazole 10 mg – 9.1%, 30 mg – 28.8%, placebo – 1.7%); akathisia (incidence with aripiprazole 10 mg – 12.1%, 30 mg – 20.3%, placebo – 1.7%).
The mean change in body weight in adolescents with bipolar I disorder at week 12 and week 30 of aripiprazole treatment was 2.4 kg and 5.8 kg, respectively, and for placebo – 0.2 kg and 2.3 kg, respectively. In the pediatric population, somnolence and fatigue were more frequently observed in patients with bipolar disorder compared to schizophrenia. In pediatric patients aged 10-17 years with drug exposure up to 30 weeks, the frequency of decreased prolactin levels in girls (<3 ng/mL) and boys (<2 ng/mL) was 28.0% and 53.3%, respectively.

Pathological gambling and other impulse control disorders
Patients taking aripiprazole may experience pathological gambling, increased sexual desire (hypersexuality), tendency to compulsive shopping, and compulsive overeating.

Shelf life:
3 years.

Storage conditions:
Store in a place inaccessible to children, in the original packaging at a temperature not exceeding 25°C.

Packaging:
10 tablets per blister. 1, 3, or 6 blisters per cardboard box.

Prescription category:
Prescription only.

Manufacturer:
LLC "Pharma Start".

Manufacturer's location and address of business activity:
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.