Aripikad

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Aripicad (Aripicad)

Composition:

Active ingredient: aripiprazole;

1 tablet contains aripiprazole 10 mg or 30 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, corn starch, magnesium stearate, iron oxide red (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

• 10 mg tablets: rectangular, uncoated, pink-colored tablets with engraving «C173» on one side;
• 30 mg tablets: round, uncoated, pink-colored tablets with engraving «C176» on one side.

Pharmacotherapeutic group. Psycholeptics. Antipsychotic agents. Other antipsychotics. Aripiprazole. ATC code N05A X12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

It is hypothesized that the efficacy of aripiprazole in schizophrenia and bipolar I disorder is mediated through a combination of its activity as a partial agonist at dopamine D2 and serotonin 5HT1 receptors, and as an antagonist at serotonin 5HT2 receptors. Aripiprazole exhibits antagonist properties in animals with dopaminergic hyperactivity and agonist properties in animals with dopaminergic hypoactivity. Aripiprazole shows high binding affinity in vitro for dopamine D2 and D3 receptors, serotonin 5HT1a and 5HT2 receptors, and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic, and histamine H1 receptors. Aripiprazole also shows moderate binding affinity for serotonin reuptake inhibition and no notable affinity for muscarinic receptors. Interactions with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

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

Clinical efficacy and safety

Adult patients

Schizophrenia

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1228 adult patients with schizophrenia and positive or negative symptoms, aripiprazole was associated with statistically significant improvement in psychotic symptoms compared to placebo.

Aripiprazole is effective in maintaining clinical improvement during continued treatment in adult patients who have shown an initial response to therapy. In a haloperidol-controlled study, the proportion of patients who responded to treatment and maintained response at 52 weeks was similar in both groups (aripiprazole 77 %, haloperidol 73 %). The overall discontinuation rate was significantly higher in patients receiving aripiprazole (43 %) than in those receiving haloperidol (30 %). Actual scores on rating scales used as secondary endpoints, including the PANSS and the Montgomery-Åsberg Depression Rating Scale (MADRS), showed significant improvement compared to haloperidol.

In a 26-week placebo-controlled trial involving adult patients with chronic stabilized schizophrenia, aripiprazole significantly reduced the relapse rate: 34 % in the aripiprazole group versus 57 % in the placebo group.

Weight gain

Aripiprazole has been shown not to cause clinically significant weight gain. In a 26-week, double-blind, multinational, olanzapine-controlled schizophrenia trial involving 314 adult patients, with weight gain as the primary endpoint, significantly fewer patients had at least 7 % weight gain from baseline (i.e., at least 5.6 kg increase for 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

Aripiprazole does not cause clinically significant changes in total cholesterol, triglycerides, high-density lipoprotein (HDL), or low-density lipoprotein (LDL) levels.

Prolactin

Prolactin levels were evaluated in all trials across all aripiprazole doses (n = 28242). The incidence of hyperprolactinemia or increased serum prolactin levels in patients receiving aripiprazole (0.3 %) was similar to that in the placebo group (0.2 %). In patients receiving aripiprazole, the mean time to onset was 42 days and the mean 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 placebo-treated patients. In patients receiving aripiprazole, the mean time to onset was 30 days and the mean duration was 194 days.

Manic episodes in bipolar I disorder

In two 3-week, placebo-controlled, flexible-dose monotherapy trials involving patients with manic or mixed episodes of bipolar I disorder, aripiprazole demonstrated superior efficacy compared to placebo in reducing manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without rapid cycling. In one 3-week, placebo-controlled, fixed-dose monotherapy trial involving patients with manic or mixed episodes of bipolar I disorder, aripiprazole did not demonstrate superior efficacy compared to placebo.

In two 12-week, placebo- and active-controlled monotherapy trials involving patients with manic or mixed episodes of bipolar I disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy compared to placebo by week 3 and maintained efficacy comparable to lithium or haloperidol by week 12. Aripiprazole also demonstrated a comparable proportion of patients achieving symptomatic remission of mania compared to lithium or haloperidol at week 12.

In a 6-week, placebo-controlled trial involving patients with manic or mixed episodes of bipolar I disorder, with or without psychotic features, who showed partial non-response to monotherapy with lithium or valproate over 2 weeks at therapeutic serum levels, adding aripiprazole as adjunctive therapy resulted in greater efficacy in reducing manic symptoms compared to monotherapy with lithium or valproate.

In a 26-week, placebo-controlled trial with a subsequent 74-week extension involving manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomization, aripiprazole demonstrated superiority over placebo in preventing relapse of bipolar disorder, primarily in preventing manic relapse, but failed to demonstrate superiority over placebo in preventing depressive relapse.

In a 52-week, placebo-controlled trial involving patients with current manic or mixed episodes of bipolar I disorder who achieved sustained remission (Young Mania Rating Scale [YMRS] and MADRS total score ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) in combination with lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated a 46 % reduction in risk (risk ratio 0.54) in preventing bipolar relapse and a 65 % reduction in risk (risk ratio 0.35) in preventing manic relapse compared to adjunctive placebo, but failed to demonstrate superiority over placebo in preventing depressive relapse. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure of Clinical Global Impression - Bipolar version (CGI-BP) Severity of Illness (SOI; mania). In this trial, investigators assigned patients to open-label monotherapy with lithium or valproate to establish partial non-response. Patients were stabilized for at least 12 consecutive weeks with a combination of aripiprazole and the same mood stabilizer. Then, stabilized patients were randomized to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were evaluated during the randomized phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. Kaplan-Meier estimates for relapse of any mood episode in the adjunctive treatment group were 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.

Pediatric patients

Schizophrenia in adolescents

In a 6-week, placebo-controlled trial involving 302 adolescents (aged 13 to 17 years) with schizophrenia and positive or negative symptoms, aripiprazole was associated with statistically significant improvement in psychotic symptoms compared to placebo. In a subgroup analysis of adolescents aged 15 to 17 years, representing 74 % of the total population, sustained efficacy was observed during a 26-week open-label extension study.

In a randomized, double-blind, placebo-controlled trial lasting 60–89 weeks involving adolescents (n = 146; aged 13 to 17 years) with schizophrenia, a statistically significant difference in the rate of relapse of psychotic symptoms was observed between the aripiprazole group (19.39 %) and the placebo group (37.50 %). The point estimate of the hazard ratio (HR) was 0.461 (95 % confidence interval, 0.242 to 0.879) in the full population. In the subgroup analysis, the point estimate of the HR was 0.495 for subjects aged 13 to 14 years compared to 0.454 for subjects aged 15 to 17 years. However, the HR estimate for the younger (13–14 years) group was imprecise, reflecting the smaller number of subjects in this group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimate (0.151 to 1.628) did not allow conclusions about treatment effect. Conversely, the 95 % confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242–0.879, and thus a treatment effect could be concluded in older patients.

Manic episodes in bipolar disorder in children and adolescents

Aripiprazole was studied in a 30-week, placebo-controlled trial involving 296 children and adolescents (aged 10 to 17 years) meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features and with a baseline YMRS score ≥ 20. Among patients included in the primary efficacy analysis, 139 patients had a current comorbid diagnosis of ADHD.

Aripiprazole was superior to placebo in change from baseline in total Y-MRS score at week 4 and week 12. In a subgroup analysis, improvement compared to placebo was more pronounced in patients with comorbid ADHD compared to the non-ADHD group, where no differences from placebo were observed. Relapse prevention has not been established.

The most common treatment-emergent adverse reactions among patients receiving 30 mg tablets were: extrapyramidal disorder (28.3 %), somnolence (27.3 %), headache (23.2 %), and nausea (14.1 %). Mean weight gain over 30 weeks of treatment was 2.9 kg compared to 0.98 kg in placebo-treated patients.

Irritability associated with autistic disorder in pediatric patients (see section “Dosage and administration”)

Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2 mg/day to 15 mg/day) and one fixed-dose (5 mg/day, 10 mg/day, or 15 mg/day)] and one 52-week open-label trial. Dosing in these trials started at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly steps to the target dose. Over 75 % of patients were under 13 years of age. Aripiprazole demonstrated statistically greater efficacy compared to placebo on the Aberrant Behavior Checklist subscale “Irritability.” However, the clinical significance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In pooled trials, the frequency of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) in patients receiving aripiprazole was 27/46 (58.7 %) and 258/298 (86.6 %), respectively. In placebo-controlled trials, mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole.

Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After 13–26 weeks of stabilization on aripiprazole (2 mg/day to 15 mg/day), patients with stable response either continued aripiprazole or were switched to placebo for the next 16 weeks. The Kaplan-Meier relapse rate at week 16 was 35 % for aripiprazole and 52 % for placebo; the risk ratio for relapse over 16 weeks (aripiprazole/placebo) was 0.57 (statistically non-significant difference). Mean weight gain during the stabilization phase (up to 26 weeks) on aripiprazole was 3.2 kg, and further mean weight gain of 2.2 kg for aripiprazole compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the study. Extrapyramidal symptoms were mainly observed during the stabilization phase in 17 % of patients, with tremor in 6.5 %.

Based on study results, aripiprazole demonstrated statistically greater efficacy compared to placebo.

Tics associated with Tourette’s disorder in pediatric patients (see section “Dosage and administration”)

The efficacy of aripiprazole was studied in children with Tourette’s syndrome (aripiprazole: n = 99, placebo: n = 44) in a randomized, double-blind, placebo-controlled, 8-week trial using a fixed-dose regimen, with a dose range of 5 mg/day to 20 mg/day and an initial dose of 2 mg. Patients were aged 7 to 17 years and had a mean baseline score of 30 on the Yale Global Tic Severity Scale (YGTSS). Aripiprazole demonstrated improvement in YGTSS change from baseline to week 8 of 13.35 in the low-dose group (5 mg or 10 mg) and 16.94 in the high-dose group (10 mg or 20 mg) compared to an improvement of 7.09 in the placebo group.

The efficacy of aripiprazole in pediatric patients with Tourette’s syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated in a flexible dose range of 2 mg/day to 20 mg/day and an initial dose of 2 mg in a 10-week, randomized, double-blind, placebo-controlled trial conducted in South Korea. Patients were aged 6 to 18 years and had a mean baseline YGTSS score of 29. The aripiprazole group demonstrated an improvement of 14.97 in YGTSS change from baseline to week 10 compared to an improvement of 9.62 in the placebo group.

In both of these short-term trials, the clinical significance of the efficacy results was not established, considering the magnitude of treatment effect compared to the large placebo effect and unclear effects on psychosocial functioning. There are no long-term data on the efficacy and safety of aripiprazole in this fluctuating disorder.

The European Medicines Agency has deferred the obligation to submit results of studies with the original medicinal product in one or more pediatric subpopulations for the treatment of schizophrenia and bipolar affective disorder (see section “Dosage and administration” for information on use in children).

Pharmacokinetics.

Absorption

Aripiprazole is well absorbed, and peak plasma concentration occurs within 3–5 hours after dosing. Aripiprazole undergoes minimal first-pass metabolism. The absolute bioavailability of the tablet formulation is 87 %. Food with high fat content does not affect the pharmacokinetic properties 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 concentrations, more than 99 % of aripiprazole and dehydro-aripiprazole are bound to plasma proteins, primarily to albumin.

Biotransformation

Aripiprazole is extensively metabolized in the liver, primarily via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, the enzymes CYP3A4 and CYP2D6 are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug substance in systemic circulation. At steady state, dehydro-aripiprazole, an active metabolite, accounts for approximately 40 % of the AUC of aripiprazole in plasma.

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, and is primarily hepatic.

After a single oral dose of aripiprazole, approximately 27 % is excreted in urine and approximately 60 % in feces. Less than 1 % of unchanged aripiprazole is excreted in urine, and approximately 18 % of the administered dose is excreted unchanged in feces.

Children

The pharmacokinetic properties of aripiprazole and hydro-aripiprazole in patients aged 10 to 17 years were similar to those in adults when adjusted for body weight.

Geriatric patients

No differences in the pharmacokinetic properties of aripiprazole were observed between healthy geriatric patients and children; there was no notable effect of patient age on the pharmacokinetic analysis in patients with schizophrenia.

Gender

No differences in the pharmacokinetic properties of aripiprazole were observed between healthy male and female subjects; there was no notable effect of gender on the pharmacokinetic analysis in patients with schizophrenia.

Smoking

Assessment of patient groups did not reveal any evidence of clinically significant effects of smoking on the pharmacokinetic properties of aripiprazole.

Race

Assessment of patient groups did not reveal any evidence of clinically significant effects of race on the pharmacokinetic properties of aripiprazole.

Renal impairment

The pharmacokinetic characteristics of aripiprazole and hydro-aripiprazole were similar in patients with acute renal disease compared to young healthy subjects.

Hepatic impairment

A single-dose clinical study in patients with varying degrees of liver cirrhosis (Child-Pugh classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetic properties of aripiprazole and hydro-aripiprazole; however, the study included only 3 patients with Child-Pugh class C cirrhosis, which is insufficient to draw conclusions about their metabolic capacity.

Clinical characteristics.

Indications.

Aripikad is indicated for the treatment of schizophrenia in adults and adolescents aged 15 years and older.

Aripikad is indicated for the treatment of moderate to severe manic episodes in bipolar I disorder, as well as for the prevention of new manic episodes in adults who have previously experienced manic episodes and responded to aripiprazole treatment (see section "Pharmacological properties").

Aripikad is indicated for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older with bipolar I disorder for up to 12 weeks (see section "Pharmacological properties").

Contraindications.

Hypersensitivity to aripiprazole or to any of the excipients of the product.

Interaction with other medicinal products and other forms of interaction.

Due to α1-adrenergic receptor antagonism, aripiprazole may enhance the effect of certain antihypertensive agents.

Because of the primary effect of aripiprazole on the central nervous system (CNS), caution should be exercised when prescribing aripiprazole concomitantly with other CNS-active medicinal products due to possible additive adverse reactions, such as sedation (see section "Adverse reactions").

Alcohol consumption should also be avoided during aripiprazole therapy. Aripiprazole should be used with caution in combination with other medicinal products that prolong the QT interval or disturb electrolyte balance.

Potential effect of other medicinal products on aripiprazole.

The H2-histamine receptor antagonist famotidine, an inhibitor of gastric acid secretion, reduces the absorption rate of aripiprazole, but this effect is not considered clinically significant. Aripiprazole is metabolized via multiple pathways involving CYP2D6 and CYP3A4 enzymes, but not CYP1A enzymes. Therefore, dose adjustment is not required in smokers.

Quinidine and other CYP2D6 inhibitors.

Potent CYP2D6 inhibitors (quinidine) increase aripiprazole AUC by 107%, while maximum concentration (Cmax) remains unchanged.

AUC and Cmax of dehydroaripiprazole, the active metabolite, decrease by 32% and 47%, respectively. The aripiprazole dose should be reduced by half when coadministered with quinidine. Other CYP2D6 inhibitors such as fluoxetine and paroxetine may have similar effects, and dose reduction of aripiprazole may be necessary.

Ketoconazole and other CYP3A4 inhibitors.

Studies have shown that potent CYP3A4 inhibitors (ketoconazole) increase aripiprazole AUC and Cmax by 63% and 37%, respectively. AUC and Cmax of dehydroaripiprazole increase by 77% and 43%, respectively. Concomitant use of potent CYP3A4 inhibitors may lead to increased plasma concentrations of aripiprazole. When coadministering ketoconazole or other potent CYP3A4 inhibitors, the potential benefits and possible risks for the patient should be carefully considered. When coadministered with ketoconazole, the recommended dose of aripiprazole should be reduced by approximately half. Similar effects are expected with other potent CYP3A4 inhibitors such as itraconazole or HIV protease inhibitors; therefore, dose reduction is also required. After discontinuation of CYP2D6 or CYP3A4 inhibitors, the aripiprazole dose should be increased to the initial level. With concomitant use of weak CYP3A4 inhibitors (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram), a moderate increase in aripiprazole concentration can be expected.

Carbamazepine and other CYP3A4 inducers.

When carbamazepine, a potent CYP3A4 inducer, was coadministered with oral aripiprazole in patients with schizophrenia and schizoaffective disorder, geometric mean Cmax and AUC of aripiprazole were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. Geometric mean Cmax and AUC of dehydroaripiprazole were reduced by 69% and 71%, respectively, during coadministration with carbamazepine compared to aripiprazole monotherapy.

The dose of aripiprazole should be doubled when coadministered with carbamazepine. Other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s wort) are theoretically expected to have a similar effect; therefore, appropriate dose increase of aripiprazole is required. After discontinuation of potent CYP3A4 inducers, the aripiprazole dose should be reduced to the recommended level.

Valproate and lithium.

No clinically significant changes in aripiprazole concentration were observed when valproate or lithium was coadministered with aripiprazole; therefore, dose adjustment is not required.

Potential effect of aripiprazole on other medicinal products.

At doses of 10–30 mg/day, aripiprazole has no effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan). Furthermore, aripiprazole and its main metabolite dehydroaripiprazole do not affect CYP1A2 enzyme activity in vitro. The likelihood of clinically significant effects of aripiprazole on medicinal products metabolized by these enzymes is low. Thus, aripiprazole does not cause clinically significant interactions mediated by these enzymes.

When aripiprazole is used concomitantly with valproate, lithium, or lamotrigine, no clinically important changes in valproate, lithium, or lamotrigine concentrations occur.

Serotonin syndrome.

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

Special precautions for use.

Improvement in the patient's clinical condition during treatment with antipsychotics may take from several days to several weeks. During this period, careful monitoring of patients is required.

Suicidal tendency: suicidal behavior is characteristic of patients with psychotic disorders and affective disorders, and in some cases has been observed shortly after initiation of antipsychotic therapy or switching from one antipsychotic to another, including treatment with aripiprazole (see section "Adverse reactions"). Antipsychotic treatment should be accompanied by careful monitoring of patients belonging to high-risk groups.

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 treatment with aripiprazole, and all preventive measures should be taken.

QT interval prolongation: the frequency of QT interval prolongation during treatment with aripiprazole was comparable to that with placebo. However, caution should be exercised when using aripiprazole in patients with a family history of QT interval prolongation (see section "Adverse reactions").

Tardive dyskinesia: tardive dyskinesia symptoms have been rarely reported in patients treated with aripiprazole for up to one year. If symptoms of tardive dyskinesia occur in a patient taking aripiprazole, dose reduction or discontinuation of treatment should be considered (see section "Adverse reactions"). These symptoms may temporarily worsen or even appear after discontinuation.

Other extrapyramidal symptoms: akathisia and parkinsonism have been observed during aripiprazole use in children. If signs of other extrapyramidal symptoms occur, dose reduction should be considered and careful clinical monitoring of the patient should be maintained.

Neuroleptic Malignant Syndrome (NMS): a life-threatening symptom complex known as neuroleptic malignant syndrome has been described during treatment with antipsychotics, including aripiprazole. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and signs of autonomic nervous system dysfunction (irregular pulse or blood pressure, tachycardia, diaphoresis, 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 also been observed. If a patient develops symptoms of NMS or unexplained very high body temperature without additional clinical manifestations of NMS, all antipsychotic medications, including aripiprazole, should be discontinued.

Seizures: seizures were infrequently reported in clinical trials of aripiprazole. Therefore, aripiprazole should be used with caution in patients with a history of seizures or conditions associated with seizure occurrence (see section "Adverse reactions").

Elderly patients with psychosis associated with dementia.

Increased mortality: in clinical trials of aripiprazole in elderly patients with Alzheimer's disease (mean age 82 years), an increased risk of mortality was observed compared to placebo. The mortality rate was 3.5% with aripiprazole versus 1.7% with placebo. Causes of death included cardiovascular diseases (e.g., heart failure, sudden cardiac death) and infections (e.g., pneumonia) (see section "Adverse reactions").

Cerebrovascular adverse reactions: cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal outcomes, were observed in elderly patients (mean age 84 years; range 78–88 years). Overall, cerebrovascular adverse reactions occurred in 1.3% of patients receiving aripiprazole compared to 0.6% of those receiving placebo. This difference was not statistically significant. Additionally, during fixed-dose studies, a relationship between aripiprazole use and the occurrence of cerebrovascular adverse reactions was noted (see section "Adverse reactions").

Aripiprazole is not indicated for the treatment of patients with psychosis due to dementia.

Hyperglycemia and diabetes: 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 clinical trials of aripiprazole, no significant differences were observed in the frequency of adverse reactions related to hyperglycemia (including diabetes) or abnormal laboratory glucose parameters compared to placebo. There is no precise comparative assessment of the risks of adverse reactions related to hyperglycemia in patients using aripiprazole versus other atypical antipsychotics. Careful monitoring of patients taking any antipsychotics, including aripiprazole, is necessary, with attention to symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and regular monitoring of glucose levels is required in patients with diabetes or risk factors for developing diabetes (see section "Adverse reactions").

Hypersensitivity: hypersensitivity reactions characterized by allergic symptoms may develop during aripiprazole use (see section "Adverse reactions").

Weight gain: weight gain is frequently observed in patients with schizophrenia and bipolar mania due to comorbid conditions, use of antipsychotics known to cause weight gain, and lack of a healthy lifestyle; this phenomenon may lead to serious complications. Weight gain has been reported in the post-marketing period among patients receiving aripiprazole. During aripiprazole treatment, weight gain typically occurred in patients with significant risk factors, such as diabetes, thyroid disorders, or pituitary adenoma in their history.

Clinical studies have not shown that aripiprazole causes clinically significant weight gain in adults (see section "Pharmacodynamics"). In studies involving adolescent patients with bipolar mania, weight gain was observed during aripiprazole treatment after 4 weeks of therapy. Body weight should be monitored in adolescents with bipolar mania. Dose reduction may be indicated in cases of significant weight gain (see section "Adverse reactions").

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

Pathological gambling: patients may experience increased episodes of pathological gambling and inability to control these impulses during aripiprazole treatment. Hypersexuality, uncontrollable shopping urges, binge eating or uncontrolled food cravings, and other impulse control disorders have also been reported. It is important for physicians to inform patients about the development of new or aforementioned disorders during aripiprazole treatment. It should be noted that impulse control symptoms may be related to the underlying disorder; however, cessation of impulses has sometimes been reported upon dose reduction or discontinuation of treatment. Impulse control disorders may harm the patient and others if not recognized. If such tendencies develop during aripiprazole treatment, consideration should be given to dose reduction or discontinuation of treatment (see section "Adverse reactions").

Lactose: the Arpikad medicinal product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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

Falls: aripiprazole may cause somnolence, 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., in elderly or debilitated patients; see section "Dosage and administration").

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate and well-controlled studies of aripiprazole use in pregnant women. Congenital anomalies have been reported, but a causal relationship with aripiprazole could not be established. Animal studies have not excluded a potential adverse effect on fetal development. Patients should be advised to inform their physician if they become pregnant or intend to become pregnant during aripiprazole treatment. Due to insufficient safety data in humans and problems identified in reproductive animal studies, this medicinal product should not be used during pregnancy unless the expected benefit clearly outweighs the potential risk to the fetus.

Newborns whose mothers have taken antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, careful monitoring of such newborns is required (see section "Adverse reactions").

Period of breastfeeding.

Aripiprazole passes into breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from aripiprazole therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

According to reproductive toxicity studies, aripiprazole does not affect fertility.

Ability to affect reaction speed when driving or operating machinery.

Aripiprazole has a minor or moderate effect on the ability to drive or operate machinery due to its potential effects on the nervous system and visual organs and the occurrence of adverse reactions such as sedation, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions").

Dosage and Administration

Adults

Schizophrenia: The recommended initial dose of Aripikad is 10 or 15 mg/day, with a maintenance dose of 0.15 mg/day administered once daily, regardless of food intake. Aripikad is effective within a dosage range of 10 to 30 mg/day. Improved efficacy at doses exceeding 15 mg/day has not been demonstrated, although higher doses may be beneficial for some individual patients. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder: The recommended initial dose of Aripikad is 15 mg once daily, regardless of food intake, as monotherapy or in combination therapy (see section "Pharmacological properties"). Higher doses may be beneficial for some individual patients. The maximum daily dose should not exceed 30 mg.

Prevention of recurrent manic episodes in bipolar I disorder: To prevent relapse of manic episodes in patients receiving aripiprazole as monotherapy or combination therapy, treatment should be continued at the same dose. Dose adjustment, including dose reduction, should be considered based on clinical status.

Paediatric patients

Schizophrenia in adolescents aged 15 years and older: The recommended dose of aripiprazole is 10 mg once daily, regardless of food intake. Treatment should be initiated at a dose of 2 mg (using aripiprazole oral solution 1 mg/mL) for 2 days, followed by dose titration to 5 mg* over the next 2 days to reach the recommended daily dose of 10 mg. If necessary, further dose increases should be made in 5 mg* increments, not exceeding the maximum daily dose of 30 mg (see section "Pharmacological properties"). Aripiprazole is effective within a dosage range of 10 mg/day to 30 mg/day. Increased efficacy at doses above 10 mg/day has not been demonstrated, although some individual patients may benefit from higher doses.

Aripiprazole is not recommended for patients with schizophrenia under 15 years of age due to insufficient data on safety and efficacy (see sections "Side effects" and "Pharmacological properties").

Manic episodes in bipolar I disorder in adolescents aged 13 years and older: The recommended dose of aripiprazole is 10 mg once daily, regardless of food intake. Treatment should be initiated at a dose of 2 mg (using aripiprazole oral solution 1 mg/mL) for 2 days, followed by dose titration to 5 mg* over the next 2 days to reach the recommended daily dose of 10 mg. The duration of treatment should be the minimum necessary to control symptoms and should not exceed 12 weeks. Increased efficacy at doses above 10 mg/day has not been demonstrated, and a daily dose of 30 mg is associated with a significantly higher incidence of serious adverse reactions, including extrapyramidal symptoms, somnolence, fatigue, and weight gain (see section "Side effects"). Therefore, doses above 10 mg/day should be used only in exceptional cases and under careful clinical monitoring (see sections "Special precautions", "Side effects", and "Pharmacological properties"). Younger patients have an increased risk of adverse effects associated with aripiprazole. Therefore, aripiprazole is not recommended for patients under 13 years of age (see sections "Side effects" and "Pharmacological properties").

Agitation associated with autism: The safety and efficacy of aripiprazole in children and adolescents under 18 years of age have not yet been established. Available data are described in the section "Pharmacological properties", but dosage recommendations cannot be provided.

Tics associated with Tourette's disorder: The safety and efficacy of aripiprazole in children and adolescents aged 6 to 18 years have not yet been established. Available data are described in the section "Pharmacological properties", but dosage recommendations cannot be provided.

*Use aripiprazole formulations at appropriate dosage strengths.

Hepatic impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment. There is insufficient data to make recommendations for patients with severe hepatic impairment. Dosing should be performed with caution in these patients. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section "Pharmacological properties").

Renal impairment

Dose adjustment is not required in patients with renal impairment.

Elderly patients

The efficacy of Aripikad in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older has not been established. Due to the increased sensitivity of this patient group, a lower initial dose should be considered based on clinical factors (see section "Special precautions").

Gender

Female patients do not require dose adjustment compared to male patients (see section "Pharmacological properties").

Smoking

Based on the metabolic pathway of aripiprazole, dose adjustment for smokers is not required (see section "Interaction with other medicinal products and other forms of interaction").

Dose adjustment due to interactions

When co-administered with strong CYP3A4 or CYP2D6 inhibitors, the dose of aripiprazole should be reduced. After discontinuation of a CYP3A4 or CYP2D6 inhibitor as part of combination therapy, the dose of aripiprazole should be increased (see section "Interaction with other medicinal products and other forms of interaction").

When co-administered with strong CYP3A4 inducers, the dose of aripiprazole should be increased. After discontinuation of a CYP3A4 inducer as part of combination therapy, the dose of aripiprazole should be reduced to the recommended dose (see section "Interaction with other medicinal products and other forms of interaction").

Children.

Aripiprazole is indicated for the treatment of schizophrenia in adolescents aged 15 years and older, and for the treatment of moderate to severe manic episodes in adolescents aged 13 years and older with bipolar I disorder for up to 12 weeks.

Overdose.

Cases of intentional or accidental acute aripiprazole overdose, with doses up to 1260 mg, have been reported in adult patients without fatal outcome. Potentially clinically significant observed symptoms included lethargy, elevated blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea. Additionally, data on accidental overdose with aripiprazole alone (up to 195 mg) in children, without fatal outcome, have been reported. Potentially clinically significant observed symptoms included somnolence, transient loss of consciousness, and extrapyramidal symptoms.

Management of overdose should include supportive care, maintenance of airway patency, oxygenation, mechanical ventilation if necessary, and symptomatic treatment. The possibility of overdose with multiple medicinal products should be considered. Therefore, immediate cardiovascular monitoring is required, including continuous ECG monitoring to detect possible arrhythmias.

After confirmed or suspected aripiprazole overdose, close medical supervision and monitoring of the patient's condition are necessary until recovery.

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

Although information on the effect of hemodialysis in aripiprazole overdose is lacking, hemodialysis is unlikely to be beneficial in treating overdose, as aripiprazole is highly protein-bound in plasma.

Adverse Reactions.

Summary of safety profile.

The most commonly observed adverse reactions were akathisia and nausea. Each of these symptoms occurred in more than 3% of patients treated with oral aripiprazole.

List of adverse reactions.

The table below presents adverse events observed during clinical trials and post-marketing use of aripiprazole.

All adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

The frequency of adverse reactions reported during the post-marketing period cannot be estimated reliably, as they are derived from spontaneous reports; therefore, the frequency of these adverse reactions is classified as not known.

System Organ Class	Common	Uncommon	Frequency not known
Blood and lymphatic system disorders			Leukopenia, neutropenia, thrombocytopenia
Immune system disorders			Allergic reactions (e.g. anaphylactic reactions; angioneurotic edema, including tongue swelling; tongue swelling, facial swelling, pruritus or urticaria)
Endocrine disorders		Hyperprolactinemia, decreased prolactin levels in blood	Hyperosmolar hyperglycemic state, diabetic ketoacidosis
Metabolism and nutrition disorders	Diabetes mellitus	Hypoglycemia	Hyponatremia, anorexia
Psychiatric disorders	Insomnia, restlessness, agitation	Depression, hypersexuality	Suicide attempts, suicidal ideation and completed suicide (see section "Special warnings and precautions for use"), pathological gambling, impulse control disorders, compulsive overeating, irresistible urge to shop, pyromania, aggression, agitation, nervousness
Nervous system disorders	Akathisia, extrapyramidal disorders, tremor, headache, sedation, somnolence, dizziness	Tardive dyskinesia, dystonia, restless legs syndrome	Neuroleptic malignant syndrome (NMS), grand mal convulsion, serotonin syndrome, speech disorder
Eye disorders	Blurred vision	Diplopia, photophobia	Oculogyric crisis
Cardiac disorders		Tachycardia	Sudden death, torsades de pointes, ventricular arrhythmia, cardiac arrest, bradycardia
Vascular disorders		Orthostatic hypotension	Venous thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, syncope
Respiratory, thoracic and mediastinal disorders		Hiccups	Aspiration pneumonia, laryngospasm, oropharyngeal spasm
Gastrointestinal disorders	Constipation, dyspepsia, nausea, hypersalivation, vomiting		Pancreatitis, dysphagia, diarrhea, abdominal discomfort, stomach discomfort
Hepatobiliary disorders			Hepatic failure, hepatitis, jaundice
Skin and subcutaneous tissue disorders			Rash, photosensitivity reactions, alopecia, increased sweating, drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders			Rhabdomyolysis, myalgia, muscle rigidity
Renal and urinary disorders			Urinary incontinence, urinary retention
Pregnancy, postpartum and perinatal conditions			Neonatal withdrawal syndrome (see section "Use during pregnancy or breastfeeding")
Reproductive system and breast disorders			Priapism
General disorders and administration site conditions	Fatigue		Thermoregulatory disorders (e.g. hypothermia, pyrexia), chest pain, peripheral edema
Investigations			Decreased body weight, increased body weight, increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels, increased gamma-glutamyl transferase (GGT) levels, increased alkaline phosphatase levels, QT interval prolongation, increased blood glucose levels, increased glycated hemoglobin levels, blood glucose fluctuations, increased creatine phosphokinase levels

Description of selected adverse reactions

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 and 15.1% for patients receiving olanzapine.

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 phase of a study, 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 and 3.0% in the placebo group.

Dystonia

Class effect: in susceptible patients, symptoms of dystonia, characterized by prolonged abnormal contractions of muscle groups, may occur during the first few days of treatment. Symptoms of dystonia include neck muscle spasms, sometimes progressing to throat tightness, difficulty swallowing, breathing difficulties, and/or tongue protrusion. Although these symptoms may occur at low doses, they are more frequent and severe at higher doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger age groups.

Prolactin

In clinical trials conducted for approved indications and during the post-marketing period, both increases and decreases in serum prolactin levels compared to baseline have been observed (see section "Pharmacodynamics").

Laboratory parameters

Comparison of laboratory parameters (including lipid profile) in patients receiving aripiprazole and placebo (see section "Pharmacodynamics") revealed no potentially clinically significant differences. Increases in creatine phosphokinase (CPK) levels, mostly transient and asymptomatic, were observed in 3.5% of patients taking aripiprazole, compared to 2.0% in the placebo group.

Paediatric patients

Schizophrenia in adolescents aged 15 years and older

In a short-term placebo-controlled clinical trial involving 302 adolescents (aged 13 to 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults, except for the following reactions, which were more frequently observed in adolescents than in adults receiving aripiprazole (more frequently than with placebo).

Somnolence/sedation and extrapyramidal disorders (very common), as well as dry mouth, increased appetite, and orthostatic hypotension (common) were reported very frequently. The safety profile of the medicinal product determined in a 26-week open-label study was similar to that observed 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 adverse reactions, which occurred commonly and more frequently in children and adolescents compared to the placebo group: weight decrease, increased blood insulin levels, arrhythmia, and leukopenia (common).

In the pooled group of adolescents with schizophrenia aged 13–17 years exposed to the drug for up to 2 years, the frequency of prolactin level decrease 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 of aripiprazole for up to 72 months, the frequency of prolactin level decrease 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 prolactin level decrease 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 and older

The frequency and type of adverse reactions in adolescents with bipolar I disorder were similar to those in adults, except for the following adverse reactions: 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, palpitations, weight gain, increased appetite, muscle twitching, and dyskinesia.

Adverse reactions that 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, compared to 0.2 kg and 2.3 kg in the placebo group.

Somnolence and fatigue were more frequently observed in the paediatric population with bipolar disorder compared to schizophrenia.

In paediatric patients aged 10–17 years exposed to the drug for up to 30 weeks, the frequency of prolactin level decrease 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 libido (hypersexuality), compulsive shopping, and compulsive overeating.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Information on any suspected adverse reactions should be reported in accordance with legislative requirements.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging.

10 tablets in a blister; 3 or 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Cadila Pharmaceuticals Limited.

Manufacturer's address and place of business.

1389, Trasad Road, Dholka – 382 225, Ahmedabad, Gujarat, India.