Zicalor®

Composition:

Active substance: aripiprazole;

1 tablet contains aripiprazole 5 mg or 10 mg, or 15 mg, or 30 mg;

Excipients: lactose monohydrate; microcrystalline cellulose (type 101); hydroxypropylcellulose; maize starch; sodium croscarmellose; magnesium stearate; colourants: indigo carmine (E 132) (for 5 mg); iron oxide yellow (E 172) (for 15 mg); iron oxide red (E 172) (for 10 mg and 30 mg).

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: blue rectangular tablets with rounded edges, approximately 8.0 x 4.5 mm in size;

10 mg tablets: pink rectangular tablets with rounded edges, approximately 8.5 x 4.0 mm in size, with a break line on one side (the tablet can be divided into two equal parts);

15 mg tablets: light yellow, round tablets with an approximate diameter of 7.0 mm;

30 mg tablets: pink, round tablets with an approximate diameter of 9.5 mm, with a break line on one side (the tablet can be divided into two equal parts).

Pharmacotherapeutic group. Psycholeptics. Other antipsychotics. 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 5HT1A receptors, and as an antagonist at serotonin 5HT2A receptors. Aripiprazole exhibits antagonist properties in animals with dopaminergic hyperactivity and agonist properties in animals with dopaminergic hypoactivity. Aripiprazole shows high in vitro binding affinity for dopamine D2 and D3 receptors, serotonin 5-HT1A and 5-HT2A receptors, as well as moderate affinity for dopamine D4 receptors, serotonin 5-HT2C and 5-HT7 receptors, alpha-1 adrenergic receptors, and histamine H1 receptors. Aripiprazole also demonstrates moderate binding affinity for serotonin reuptake and lacks significant affinity for muscarinic receptors. Interactions with other receptors, besides the aforementioned subtypes of dopamine and serotonin receptors, may explain some of the other clinical effects of aripiprazole. Aripiprazole administered to healthy volunteers at doses ranging from 0.5 mg to 30 mg once daily for 2 weeks resulted in a dose-dependent reduction in 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 treatment in adult patients who showed an initial response to therapy. In a controlled study using haloperidol as the active comparator, the proportion of patients who responded to treatment 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 completion rate was significantly higher in patients receiving aripiprazole (43%) compared to those receiving haloperidol (30%). Actual scores on assessment scales, including the PANSS (Positive and Negative Syndrome Scale) and the 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. Clinically significant weight gain associated with aripiprazole was not observed in clinical trials. In a 26-week controlled (active comparator: olanzapine), double-blind, multinational schizophrenia study involving 314 patients and using weight gain as the primary endpoint, significantly fewer patients gained at least 7% of their baseline body 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 pooled analysis of lipid parameters obtained from placebo-controlled clinical trials 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 mean time to onset of such changes 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 the placebo group. In patients receiving aripiprazole, the mean time to onset of such changes was 30 days, and the mean duration was 194 days.

Manic episodes in bipolar I disorder. In two 3-week, dose-adjusted, placebo-controlled monotherapy studies involving patients with manic or mixed episodes of bipolar I disorder, aripiprazole demonstrated higher efficacy compared to placebo. Efficacy was defined as reduction in severity of manic symptoms over 3 weeks of treatment. These studies included patients with and without psychotic symptoms, as well as those with and without rapid cycling. In one 3-week, fixed-dose, placebo-controlled monotherapy study in patients with manic or mixed episodes of bipolar I disorder, aripiprazole did not demonstrate superior 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 than placebo by week 3, and maintained efficacy comparable to lithium or haloperidol by week 12. The number of patients with mania who achieved symptom remission with aripiprazole was comparable to those 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, 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 with aripiprazole during the stabilization phase were enrolled. In this study, aripiprazole was more effective than placebo in preventing relapse of bipolar disorder (primarily 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 the Young Mania Rating Scale [Y-MRS] and Montgomery-Åsberg Depression Rating Scale [MADRS] ≤ 12), adding aripiprazole (10 mg/day or 30 mg/day) to lithium or valproate for 12 weeks resulted in better outcomes compared to adding aripiprazole to placebo, with a 46% reduction in the risk of relapse of bipolar episodes (relative risk OR) and a 65% reduction in the risk of manic episode relapse (OR = 0.35). However, this combination did not surpass placebo in preventing depressive relapse. Adding aripiprazole was superior to placebo on the secondary endpoint—the Clinical Global Impression-Bipolar Version (CGI-BP) severity score. In this open-label study, patients were divided into groups receiving monotherapy with lithium or valproate to identify those with partial non-response to therapy. Patients were stabilized for at least 12 weeks by adding aripiprazole to the same mood stabilizers. Stabilized patients were then randomized in a double-blind manner to continue the same mood stabilizers with either aripiprazole or placebo. 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 analysis, 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 peak plasma concentrations reached within 3–5 hours after administration. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability of the drug after oral administration is 87%. Food intake does not affect the bioavailability of aripiprazole. Consumption of a high-fat meal does not affect the pharmacokinetics of aripiprazole.

Distribution. Aripiprazole is extensively distributed into 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 through three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies indicate that dehydrogenation and hydroxylation of aripiprazole are mediated by CYP3A4 and CYP2D6 enzymes, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the primary active substance present in systemic circulation. At steady state, dehydroaripiprazole, an 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. 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% is excreted in urine and approximately 60% in feces. Less than 1% of unchanged aripiprazole is excreted in urine, and approximately 18% of unchanged aripiprazole is excreted in feces.

Pharmacokinetics in special patient populations

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. No differences in the pharmacokinetics of aripiprazole were observed between healthy elderly volunteers and younger patients. Population pharmacokinetic analysis in patients with schizophrenia also showed no significant effect of age.

Sex. No differences in aripiprazole pharmacokinetics were observed between healthy men and women, and no significant effect of sex was observed in population pharmacokinetic analysis of patients with schizophrenia.

Smoking and race. Pharmacokinetic assessment of patient groups did not reveal clinically significant race-related differences or effects of smoking on aripiprazole pharmacokinetics.

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 3 patients with Child-Pugh class C cirrhosis were included, which is insufficient to draw conclusions about metabolic capacity.

Clinical characteristics.

Indications.

Treatment of schizophrenia in adults.

Treatment of moderate to severe manic episodes in bipolar I disorder, as well as 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 medicinal product.

Interaction with other medicinal products and other forms of interaction.

Due to antagonism at α1-adrenergic receptors, 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 administering aripiprazole concomitantly with alcohol or other CNS-acting medicinal products due to the potential for additive adverse reactions such as sedation. Aripiprazole should be used cautiously in combination with other medicinal products that prolong the QT interval or disrupt electrolyte balance.

Potential effect of other medicinal products on aripiprazole activity

The gastric 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 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. In a clinical study in healthy volunteers, the potent CYP2D6 enzyme inhibitor (quinidine) increased aripiprazole AUC by 107%, while Cmax remained unchanged. 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 coadministered with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have a similar effect; therefore, dose reduction when using these agents should be comparable.

Ketoconazole and other CYP3A4 inhibitors. In a clinical study in healthy volunteers, the potent CYP3A4 enzyme inhibitor (ketoconazole) increased aripiprazole AUC and Cmax by 63% and 37%, respectively. AUC and Cmax values of dehydroaripiprazole increased by 77% and 43%, respectively. In patients with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole compared to patients with normal CYP2D6 metabolism. When concomitant use of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefit should outweigh the possible risk to the patient. When aripiprazole is coadministered 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 a similar effect; therefore, dose reductions should be made accordingly (see section "Dosage and administration"). After discontinuation of a CYP2D6 or CYP3A4 inhibitor, the aripiprazole dose should be increased to the level used prior to initiation of concomitant therapy. A slight increase in aripiprazole concentration may occur with concomitant use of weak CYP3A4 inhibitors (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram).

Carbamazepine and other CYP3A4 inducers. Following coadministration of carbamazepine, a potent CYP3A4 inducer, with aripiprazole in patients with schizophrenia or schizoaffective disorder, geometric mean values of Cmax and AUC of aripiprazole decreased by 68% and 73%, respectively, compared to monotherapy with aripiprazole (30 mg). Similarly, when carbamazepine was coadministered with dehydroaripiprazole, geometric mean values of Cmax and AUC decreased by 69% and 71%, respectively, compared to aripiprazole monotherapy. The dose of aripiprazole should be doubled when coadministered with carbamazepine. Concomitant use of aripiprazole with other potent CYP3A4 inducers (rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s wort) that theoretically have a similar effect requires appropriate dose escalation. 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 were coadministered with aripiprazole; therefore, dose adjustment is not required when valproate or lithium are used concomitantly with aripiprazole.

Potential effect of aripiprazole on the activity of other medicinal products

In clinical studies, aripiprazole at doses of 10–30 mg/day did not affect the metabolism of substrates of the CYP2D6 enzyme (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan). Furthermore, in vitro studies showed no capacity of aripiprazole or dehydroaripiprazole to influence metabolic pathways mediated by the CYP1A2 enzyme. Therefore, it is unlikely that aripiprazole causes clinically significant drug interactions mediated by these enzymes. No clinically significant changes in valproate, lithium, or lamotrigine concentrations were observed when coadministered with aripiprazole.

Serotonin syndrome. Cases of serotonin syndrome have been reported in patients taking aripiprazole, particularly when used concomitantly with other serotonergic agents, including selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs), or with agents that increase aripiprazole concentration.

Special precautions for use.

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

Suicidal tendencies. Suicidal behaviour is characteristic of patients with psychotic disorders and affective disorders, and has been observed shortly after initiation of antipsychotic therapy or switching from one antipsychotic to another, including treatment with aripiprazole. 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 arterial hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or arterial hypertension, including progressive or malignant hypertension. Venous thromboembolism (VTE) has been reported during antipsychotic treatment. Since acquired VTE risk factors are often observed in patients taking antipsychotics, all possible VTE risk factors should be identified before and during aripiprazole treatment, and all preventive measures should be taken.

QT interval prolongation. In clinical trials 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 "Adverse reactions").

Tardive dyskinesia. During clinical trials lasting one year or less, reports of dyskinesia with aripiprazole use were infrequent. 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 transiently worsen or even emerge after discontinuation of treatment.

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). NMS is a potentially fatal syndrome associated with the use of antipsychotic drugs. In clinical trials of aripiprazole, NMS occurred rarely. 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, 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 and rhabdomyolysis, not necessarily associated with NMS, have also been reported. If a patient develops symptoms of NMS or unexplained very high body temperature without additional clinical signs of NMS, all antipsychotic drugs, including aripiprazole, should be discontinued immediately.

Seizures. Seizures have been infrequently observed during aripiprazole treatment. Therefore, aripiprazole should be used with caution in patients with a history of epilepsy or conditions associated with seizures (see section "Adverse reactions").

Elderly patients with psychosis associated with dementia

Increased mortality. In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56 to 99 years), the use of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease was associated with an increased risk of mortality compared to placebo. Mortality in patients receiving aripiprazole was 3.5% compared to 1.7% in the placebo group. Although causes of death varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) origin (see section "Adverse reactions").

Cerebrovascular adverse reactions. In these same clinical trials, cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal cases (mean age 84 years, age range 78–88 years), were reported. Overall, cerebrovascular adverse reactions occurred in 1.3% of patients taking aripiprazole compared to 0.6% in the placebo group. This difference was not statistically significant. However, in one of these trials (fixed-dose study), a clear dose-dependent relationship between aripiprazole dose and the occurrence of cerebrovascular adverse events was observed. 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 reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and family history of diabetes. In clinical trials of aripiprazole, no significant differences in the frequency of adverse reactions related to hyperglycemia (including diabetes mellitus) or abnormal laboratory glucose parameters were observed compared to placebo. There is no precise comparative assessment of the risks of hyperglycemia-related adverse reactions in patients treated with aripiprazole versus other atypical antipsychotics. Careful monitoring of patients taking any antipsychotic, including aripiprazole, is necessary, with attention to symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes or risk factors for diabetes should be regularly monitored for increased glucose levels (see section "Adverse reactions").

Hypersensitivity. As with other medicinal products, hypersensitivity reactions may occur with aripiprazole, manifesting as allergic symptoms (see section "Adverse reactions").

Weight gain. Weight gain is commonly observed in patients with schizophrenia and bipolar mania due to comorbid conditions, use of antipsychotics known to cause weight gain, and negative impact on healthy lifestyle, potentially leading to serious complications. During aripiprazole treatment, weight gain was generally observed in patients with significant risk factors such as diabetes, thyroid disorders, or pituitary adenoma in their history. Clinically significant weight gain due to aripiprazole was not observed in clinical trials in adults. In clinical trials in adolescent patients with bipolar mania, aripiprazole use over 4 weeks was associated with weight gain. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain becomes clinically significant, dose reduction should be considered (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 and other impulse control disorders. Cases of pathological gambling and inability to control this behaviour have been reported in patients treated with aripiprazole. Other impulse control disorders such as hypersexuality, compulsive shopping, binge eating or uncontrolled eating, and other impulsive or compulsive behaviours have also been reported. It is important that physicians inform patients about the potential development of new or aforementioned disorders during aripiprazole treatment. Impulse control symptoms may be related to the underlying disorder, but sometimes pathological behaviours resolve with dose reduction or discontinuation of treatment. Impulse control disorders may harm the patient and others if not recognized. If such disorders develop during aripiprazole treatment, dose reduction or discontinuation of treatment should be considered.

Lactose. The medicinal product Zyklor® contains lactose. This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Patients with comorbid Attention Deficit Hyperactivity Disorder (ADHD). Despite the high prevalence of comorbid bipolar I disorder and ADHD, safety data on the concomitant use of aripiprazole and stimulants are very limited; therefore, extreme caution is required when prescribing these medicinal products together.

Falls. Aripiprazole may cause somnolence, orthostatic hypotension, and motor or 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").

The medicinal product Zyklor® contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy. Adequate and well-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 studies do not allow exclusion of potential embryofetotoxicity. Patients should inform their physician if they become pregnant or intend to become pregnant during aripiprazole treatment. Due to insufficient information on the safety of aripiprazole in humans and the ambiguous results of animal studies, the medicinal product should be used during pregnancy only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus. Newborns whose mothers have taken antipsychotics (including aripiprazole) during the third trimester of pregnancy may experience adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration after birth. Agitation, arterial hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding difficulties have been reported. Therefore, newborns should be closely monitored.

Breastfeeding. Aripiprazole/metabolites are excreted in breast milk. When deciding whether to discontinue breastfeeding or to discontinue/withhold aripiprazole, the benefit of breastfeeding for the child and the benefit of therapy for the mother should be weighed.

Fertility. Reproductive toxicity studies have shown that aripiprazole does not have a negative effect on fertility.

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage.

Schizophrenia. The recommended initial dose of Zyklor® is 10 mg or 15 mg once daily, with a maintenance dose of 15 mg once daily, regardless of food intake. Zyklor® is effective in the dose range of 10 mg to 30 mg per day. Increased efficacy with doses exceeding 15 mg daily has not been demonstrated, although higher doses may benefit some individual patients. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder. The recommended initial dose of Zyklor® is 15 mg once daily, regardless of food intake. The drug can be administered as monotherapy or as part of combination therapy. For some patients, dose escalation may be effective. 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 previously treated with aripiprazole as monotherapy or in combination therapy, treatment should be continued at the same dose. Based on the patient's clinical condition, daily dose adjustments, including dose reduction, may be considered.

Patients with hepatic impairment. Dose adjustment is not required for patients with mild to moderate hepatic impairment. Insufficient data are available to provide recommendations for patients with severe hepatic impairment. Dose selection for these patients should be made with caution. The maximum daily dose of 30 mg should be used cautiously in patients with severe hepatic impairment.

Patients with renal impairment. Dose adjustment is not required.

Elderly patients. The efficacy of Zyklor® in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older has not been established. Given the increased sensitivity of this patient population, consideration should be given to initiating treatment with a lower dose, if other clinical factors permit.

Gender. Dose adjustment based on patient gender is not required.

Smoking. Due to the metabolic pathway of Zyklor®, dose adjustment is not required for smokers.

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

Children.

Zyklor® at this dosage strength is not recommended for use in children.

Overdose.

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

Treatment. Management of overdose should include supportive care, maintenance of airway patency, oxygenation, mechanical ventilation, and symptomatic treatment. The possibility of multiple drug overdose should be considered. Therefore, immediate cardiovascular monitoring, including continuous ECG monitoring to detect possible arrhythmias, is necessary. After confirmed or suspected aripiprazole overdose, close medical supervision and monitoring of the patient are required 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%, suggesting potential efficacy of activated charcoal in overdose management.

Hemodialysis. Although there is no information on the effect of hemodialysis in treating aripiprazole overdose, hemodialysis is unlikely to be beneficial because aripiprazole is highly protein-bound in plasma.

Adverse Reactions

The most commonly reported adverse reactions in placebo-controlled trials were akathisia and nausea, each occurring in more than 3% of patients receiving oral aripiprazole. Below is the frequency of adverse reactions associated with aripiprazole therapy, based on adverse effects reported during clinical trials and/or post-marketing use. Adverse reactions are categorized by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), frequency not known (cannot be estimated from available data). The frequency of adverse reactions during post-marketing use cannot be determined because the information is derived from spontaneous reports; therefore, the frequency of these adverse reactions is classified as "not known".

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

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

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

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

Psychiatric disorders: common – insomnia, anxiety, restlessness; uncommon – depression, hypersexuality; frequency not known – suicide attempts, suicidal thoughts and suicide, pathological gambling, impulse control disorders, compulsive overeating, irresistible urge to shop, pyromania, aggression, agitation, nervousness.

Nervous system disorders: common – akathisia, extrapyramidal disorders, tremor, headache, sedation, somnolence, dizziness; uncommon – dystonia, tardive dyskinesia, restless legs syndrome; frequency not known – neuroleptic malignant syndrome, grand mal convulsions, serotonin syndrome, speech disorder.

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

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

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

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

Gastrointestinal disorders: common – constipation, dyspepsia, nausea, increased salivation, vomiting; frequency not known – pancreatitis, dysphagia, diarrhea, abdominal discomfort, gastric discomfort.

Hepatobiliary disorders: frequency not known – hepatic failure, hepatitis, jaundice.

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

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

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

Pregnancy, puerperium and perinatal conditions: frequency not known – neonatal withdrawal syndrome.

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

General disorders: common – fatigue; frequency not known – thermoregulatory disorders (hypothermia, pyrexia), chest pain, peripheral edema.

Investigations: frequency not known – weight increase, weight decrease, increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase, increased blood glucose, increased glycated hemoglobin, blood glucose fluctuations, increased creatine phosphokinase (CPK) levels, QT interval prolongation.

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% in patients treated with aripiprazole and 13.1% in patients receiving placebo. In another 26-week controlled study, the incidence of EPS was 14.8% in patients receiving aripiprazole and 15.1% in patients receiving olanzapine.

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

Akathisia. In placebo-controlled trials, 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. Dystonic symptoms, characterized by prolonged abnormal contraction of muscle groups, may occur during the first few days of treatment. Symptoms of dystonia include neck muscle spasms, sometimes progressing to throat constriction, difficulty swallowing, breathing difficulties, and tongue protrusion. Dystonia occurs more frequently and intensifies with increasing doses of antipsychotics, including aripiprazole. The risk of acute dystonia is higher in males and younger patients.

Prolactin. Aripiprazole caused changes in serum prolactin concentration (either decrease or increase) compared to baseline levels.

Laboratory parameters. No clinically significant differences in routine laboratory parameters or lipid parameters were observed between patients receiving aripiprazole and those receiving placebo. Increases in CPK levels were usually transient and asymptomatic, observed in 3.5% of patients taking aripiprazole and in 2.0% of patients receiving placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 4 years.

Storage conditions. Store in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets per blister. 3, 6, or 9 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and location of operations.
Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.