Frame®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FREYM® (FREYM)

Composition:

Active substance: aripiprazole;

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

Excipients:

Tablets 5 mg: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate; indigocarmine (E 132); vanilla flavoring (containing propylene glycol and benzyl alcohol); aspartame (E 951);

Tablets 10 mg: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate; iron oxide red (E 172); vanilla flavoring (containing propylene glycol and benzyl alcohol); aspartame (E 951);

Tablets 15 mg: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate; iron oxide yellow (E 172); vanilla flavoring (containing propylene glycol and benzyl alcohol); aspartame (E 951);

Tablets 30 mg: lactose monohydrate; microcrystalline cellulose; sodium croscarmellose; colloidal anhydrous silicon dioxide; magnesium stearate; iron oxide red (E 172); vanilla flavoring (containing propylene glycol and benzyl alcohol); aspartame (E 951).

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 5 mg — blue, rectangular, biconvex tablets, smooth on both sides;

tablets 10 mg — pink, rectangular, biconvex tablets, smooth on both sides;

tablets 15 mg — yellow, round, flat tablets, smooth on both sides;

tablets 30 mg — pink, round, flat tablets, smooth on both sides.

Pharmacotherapeutic group. Antipsychotic agents (neuroleptics).

ATC code N05AX12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The therapeutic effect of aripiprazole in schizophrenia and bipolar I disorder is mediated by a combination of partial agonist activity at D2-dopaminergic and 5HT1a-serotonergic receptors and antagonist activity at 5HT2-serotonergic receptors.

Aripiprazole has high affinity in vitro for D2- and D3-dopaminergic receptors, 5HT1a- and 5HT2a-serotonergic receptors, and moderate affinity for D4-dopaminergic, 5HT2c- and 5HT7-serotonergic receptors, α1-adrenergic receptors, and H1-histaminergic receptors. Aripiprazole also demonstrates moderate affinity for serotonin reuptake sites and lacks affinity for muscarinic receptors. In animal experiments, aripiprazole exhibited antagonism toward dopaminergic hyperactivity and agonism toward dopaminergic hypoactivity. The interaction with both dopaminergic and serotonergic receptors may explain some of the clinical effects of aripiprazole.

Clinical efficacy and safety

Adults

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 when treatment is continued in adult patients who initially responded to therapy. In a study controlled against haloperidol, the proportion of patients responding to treatment over 52 weeks was similar in both groups (aripiprazole 77% and haloperidol 73%). Overall, the final response 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 with aripiprazole compared to haloperidol.

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

Weight gain

Clinical studies have not shown that aripiprazole causes clinically significant weight gain. In a 26-week, double-blind, multinational schizophrenia trial controlled against olanzapine and involving 314 adult patients, with weight gain as the primary endpoint, significantly fewer patients experienced at least a 7% increase in body weight from baseline (i.e., an increase of at least 5.6 kg at a mean baseline 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 from placebo-controlled clinical trials in adults, aripiprazole was not shown to cause clinically significant changes in levels of total cholesterol, triglycerides, high-density lipoprotein (HDL), or low-density lipoprotein (LDL).

Prolactin

Prolactin levels were evaluated in trials 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 with placebo (0.2%). In patients receiving aripiprazole, the mean time to onset of these 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 placebo-treated patients. In patients receiving aripiprazole, the median time to onset of these changes was 30 days, and the mean duration was 194 days.

Manic episodes in bipolar I disorder

In two 3-week, flexible-dose, placebo-controlled 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, fixed-dose, placebo-controlled 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 in patients with manic or mixed episodes of bipolar I disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy compared to placebo at week 3 and maintained efficacy comparable to lithium or haloperidol at week 12. The proportion of patients achieving symptomatic remission of mania with aripiprazole at week 12 was comparable to that with lithium or haloperidol.

In a 6-week, placebo-controlled trial involving patients with manic or mixed episodes of bipolar I disorder, with or without psychotic features, who had shown only partial response to monotherapy with lithium or valproate over 2 weeks at therapeutic serum levels, the addition of 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 followed by a 74-week extension in manic patients who achieved remission on aripiprazole during the 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 in patients with current manic or mixed episodes of bipolar I disorder who achieved sustained remission (Young Mania Rating Scale [YMRS] and MADRS total scores ≤ 12) on aripiprazole (10–30 mg/day), adjunctive aripiprazole demonstrated superiority over placebo, reducing the risk of relapse by 46% (risk ratio 0.54) in preventing bipolar disorder relapse and by 65% (risk ratio 0.35) in preventing manic relapse, but did not demonstrate superiority over placebo in preventing depressive relapse. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure of the Clinical Global Impression—Bipolar version (CGI-BP) and Severity of Illness (SOI; mania). In this trial, patients received open-label monotherapy with lithium or valproate to establish partial non-response. Patients were stabilized for at least 12 consecutive weeks using a combination of aripiprazole and the same mood stabilizer. Then, stabilized patients were randomized to continue the 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. The Kaplan–Meier relapse rate for any mood episode in the adjunctive treatment group was 16% with aripiprazole + lithium and 18% with aripiprazole + valproate, compared to 45% with placebo + lithium and 19% with placebo + valproate.

Children

Schizophrenia in adolescents

In a 6-week, placebo-controlled trial involving 302 adolescent patients (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, who comprised 74% of the total enrolled population, efficacy was maintained during a 26-week open-label extension study.

In a 60–89-week, randomized, double-blind, placebo-controlled trial in 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 risk ratio (RR) was 0.461 (95% confidence interval: 0.242 to 0.879) in the full population. In a subgroup analysis, the point estimate of the heart rate (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 group (0.151 to 1.628) did not allow conclusions about treatment effect. In contrast, the 95% confidence interval for the HR in the older subgroup (aripiprazole: n = 69; placebo: n = 36) was 0.242 to 0.879, allowing conclusions about treatment effect in older patients.

Manic episodes in bipolar I 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 had a current comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD).

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

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

Irritability associated with autistic disorder in children

The effect of aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2–15 mg/day) and one fixed-dose (5 mg/day, 10 mg/day, or 15 mg/day)] and in one open-label 52-week trial. In these trials, dosing started at 2 mg/day, increased to 5 mg/day after one week, and then increased by 5 mg/day weekly steps to the target dose. Over 75% of patients were younger than 13 years. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the irritability subscale of the Aberrant Behavior Checklist. However, the clinical significance of this finding is not 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 frequencies of low serum prolactin levels (< 3 ng/mL in females and < 2 ng/mL in males) in patients receiving aripiprazole were 27/46 (58.7%) and 258/298 (86.6%), respectively. In placebo-controlled trials, mean weight gain was 0.4 kg in the placebo group and 1.6 kg in the aripiprazole group.

Aripiprazole was also studied in a placebo-controlled long-term trial. After 13–26 weeks of stabilization on aripiprazole (2–15 mg/day), patients with stable response remained on aripiprazole or were switched to placebo for the next 16 weeks. The Kaplan–Meier relapse rate at week 16 was 35% with aripiprazole and 52% in the placebo group; 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 in the aripiprazole group compared to 0.6 kg in the placebo group was observed during the second phase (16 weeks) of the study. Extrapyramidal symptoms were primarily observed during the stabilization phase in 17% of patients, with tremor occurring in 6.5%.

Tics associated with Tourette’s disorder in children

The efficacy of aripiprazole was studied in children with Tourette’s disorder (aripiprazole: n = 99, placebo: n = 44) in a randomized, double-blind, placebo-controlled 8-week trial using a fixed dose based on body weight, with doses ranging from 5 mg/day to 20 mg/day and a starting 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). With aripiprazole, improvement in the YGTSS score from baseline to week 8 was 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 children 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 with a starting 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 score of 29 on the YGTSS. In the aripiprazole group, improvement in the YGTSS score from baseline to week 10 was 14.97 compared to 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 the treatment effect compared to the large placebo effect and unclear effects on psychosocial functioning. Long-term data on the efficacy and safety of aripiprazole in this fluctuating disorder are lacking.

Pharmacokinetics.

The activity of the medicinal product is due to the active substance—aripiprazole. The mean elimination half-life of aripiprazole is approximately 75 hours. Steady-state concentration is achieved by 14 days. Accumulation of the drug with repeated administration is predictable. Pharmacokinetic parameters of aripiprazole at steady state are dose-proportional. No circadian fluctuations in the distribution of aripiprazole and its metabolite dehydro-aripiprazole have been observed.

Absorption

Aripiprazole is rapidly absorbed after administration. Maximum plasma concentration (Cmax) of aripiprazole is reached within 3–5 hours. The absolute bioavailability of the drug is 87%. Food intake does not affect the bioavailability 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, over 99% of aripiprazole is bound to serum proteins, primarily to albumin.

Biotransformation

Aripiprazole undergoes minimal presystemic metabolism. Aripiprazole is metabolized in the liver via three 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 main component of the drug in blood. At steady state, the area under the plasma concentration–time curve (AUC) of dehydro-aripiprazole is approximately 40% of the 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. After a single dose of radiolabeled [14C] aripiprazole, approximately 27% and 60% of radioactivity is recovered in urine and feces, respectively. Less than 1% of unchanged aripiprazole is found in urine, and approximately 18% of the administered dose is excreted unchanged in feces. Total clearance of aripiprazole is 0.7 mL/min/kg, primarily via hepatic elimination.

Children

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

Pharmacokinetics in special patient populations

Elderly patients

No differences in aripiprazole pharmacokinetics were observed between healthy elderly and younger volunteers, and no age effect was observed in population pharmacokinetic analysis in patients with schizophrenia.

Gender

No differences in aripiprazole pharmacokinetics were observed between healthy male and female volunteers, and no gender effect was detected in population pharmacokinetic analysis in patients with schizophrenia.

Smoking

Population pharmacokinetic assessment did not reveal any clinically significant effect of smoking on aripiprazole pharmacokinetics.

Race

No evidence of racial differences in the pharmacokinetics of aripiprazole has been identified.

Renal impairment

Pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole 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 dehydro-aripiprazole was observed. However, only three patients with Child–Pugh class C cirrhosis were included, which is insufficient to draw conclusions about metabolic capacity.

Clinical characteristics.

Indications.

For the treatment of schizophrenia in adults and adolescents aged 15 years and older.

For the treatment of moderate to severe manic episodes of bipolar I disorder and for prevention of new manic episodes in adults who have already experienced such episodes and have been previously treated with aripiprazole.

For the treatment of moderate to severe manic episodes of bipolar I disorder in adolescents aged 13 years and older for up to 12 weeks.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Aripiprazole may enhance the effect of certain antihypertensive agents due to blockade of α1-adrenergic receptors.

Due to the significant effect of aripiprazole on the central nervous system, caution should be exercised when aripiprazole is used concomitantly with alcohol and other medicinal products affecting the central nervous system, due to possible additive adverse reactions such as sedative effects (see section "Adverse reactions").

Caution should be exercised when aripiprazole is used concomitantly with medicinal products that prolong the QT interval and alter electrolyte levels.

Potential effect of other medicinal products on aripiprazole

The gastric acid secretion inhibitor, H2-histamine receptor antagonist famotidine, reduces the rate of absorption 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 the AUC of aripiprazole by 107%, while the maximum concentration (Cmax) remains unchanged.

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

Ketoconazole and other CYP3A4 inhibitors

Studies have shown that potent CYP3A4 inhibitors (ketoconazole) increase the AUC and Cmax of aripiprazole by 63% and 37%, respectively. The AUC and Cmax of dehydroaripiprazole are increased by 77% and 43%, respectively. In individuals with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may lead to increased plasma concentrations of aripiprazole. When using ketoconazole or other potent CYP3A4 inhibitors concomitantly, the potential benefits and possible risks for the patient should be carefully considered. The dose of aripiprazole should be reduced by approximately half when used concomitantly with ketoconazole. Similar effects may occur when using other potent CYP3A4 inhibitors such as itraconazole or HIV protease inhibitors, and therefore a similar dose reduction is required. After discontinuation of CYP2D6 or CYP3A4 inhibitors, the dose of aripiprazole should be increased to the initial level. When used concomitantly with weak CYP3A4 inhibitors (such as diltiazem) or weak CYP2D6 inhibitors (escitalopram), a moderate increase in aripiprazole concentration is possible.

Carbamazepine and other CYP3A4 inducers

In patients with schizophrenia or schizoaffective disorder, administration of 30 mg aripiprazole together with carbamazepine, a potent CYP3A4 inducer, resulted in a 68% and 73% reduction in Cmax and AUC of aripiprazole, respectively, and a 69% and 71% reduction in Cmax and AUC of its active metabolite dehydroaripiprazole, respectively. The dose of aripiprazole should be doubled when used concomitantly with carbamazepine. A similar effect may occur when used with other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, St. John's wort). After discontinuation of potent CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended level.

Valproate and lithium

No clinically significant effect on aripiprazole concentration was observed when valproate or lithium was co-administered with aripiprazole; therefore, dose adjustment is not required.

Potential effect of aripiprazole on other medicinal products

When aripiprazole was administered at doses of 10–30 mg/day, no effect was observed on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Furthermore, aripiprazole and its major metabolite dehydroaripiprazole do not alter CYP1A2 enzyme activity in vitro. A clinically significant effect of aripiprazole on medicinal products metabolized by these enzymes is unlikely. 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 the concentrations of valproate, lithium, or lamotrigine are observed.

Serotonin syndrome

Serotonin syndrome has been reported in patients taking aripiprazole. Manifestations of this syndrome are possible, particularly when used concomitantly with serotonergic medicinal products such as serotonin reuptake inhibitors / serotonin-norepinephrine reuptake inhibitors, or medicinal products that increase aripiprazole concentration (see section "Adverse reactions").

Special precautions for use.

Clinical improvement with antipsychotic medications may take several days or weeks. During this period, patients should be carefully monitored.

Suicidal tendencies

In some cases, immediately after initiation or when changing neuroleptic medications, including aripiprazole, suicidal behaviour characteristic of psychiatric disorders and mood changes have been observed. Patients with a high risk of suicide require careful medical supervision when treated with neuroleptics.

Cardiovascular disorders

Aripiprazole should be used with caution in patients with cardiovascular diseases (including history of myocardial infarction, ischemic heart disease, heart failure, or conduction disorders), cerebrovascular diseases, and conditions leading to arterial hypotension (dehydration, hypovolemia, and treatment with antihypertensive agents) or arterial hypertension, including exacerbations or malignant hypertension. Cases of venous thromboembolism have been reported during treatment with neuroleptics. Before and during treatment with neuroleptics, possible risk factors for venous thromboembolism should be assessed, and appropriate preventive measures taken.

QT interval prolongation

During clinical trials, the frequency of QT interval prolongation with aripiprazole was comparable to that with placebo. Aripiprazole should be used with caution in patients with a family history of QT interval prolongation.

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 receiving aripiprazole, dose reduction or discontinuation of treatment should be considered (see section "Adverse reactions"). These symptoms may transiently worsen after discontinuation of therapy or may even appear after stopping treatment.

Other extrapyramidal symptoms

In pediatric clinical trials of aripiprazole, akathisia and parkinsonism were observed. If other extrapyramidal symptoms occur, dose reduction of aripiprazole should be considered, and careful clinical monitoring of the patient should be maintained.

Malignant neuroleptic syndrome (MNS)

A life-threatening complex of symptoms known as malignant neuroleptic syndrome, which may be fatal, has been reported during treatment with neuroleptics, including aripiprazole. This syndrome is characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse and blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). In addition, elevated creatine phosphokinase activity, myoglobinuria (rhabdomyolysis), and acute renal failure may sometimes occur. However, increased creatine phosphokinase levels and rhabdomyolysis have also been reported independently of MNS. If symptoms of MNS or unexplained fever without additional clinical signs of MNS occur, all neuroleptics, including aripiprazole, should be discontinued.

Seizures

Seizures have been infrequently observed during treatment with aripiprazole. 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 studies (n = 938) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (mean age 82 years, range 56 to 99 years), an increased risk of mortality was observed. The mortality rate with aripiprazole was 3.5% compared to 1.7% with placebo. Although the causes of death varied, most were due to cardiovascular disorders (e.g., heart failure, sudden cardiac death) or infections (e.g., pneumonia) (see section "Adverse reactions").

Cerebrovascular adverse reactions

Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatal cases (mean age 84 years, range 78 to 88 years), have been reported. 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. In addition, in fixed-dose studies, a relationship between aripiprazole use and cerebrovascular adverse reactions was observed.

Aripiprazole is not indicated for the treatment of psychosis associated with dementia.

Hyperglycemia and diabetes mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, which may lead to hyperosmolar coma or even death, has been observed in patients treated with atypical neuroleptics, including aripiprazole. Risk factors that may contribute to the development of severe complications include obesity and family history of diabetes mellitus. In clinical trials, no significant differences in the frequency of adverse reactions related to hyperglycemia (including diabetes mellitus) or in laboratory abnormalities of glycemia were observed with aripiprazole compared to placebo. Precise estimates of the risk of hyperglycemia-related adverse reactions in patients treated with aripiprazole and other atypical antipsychotics are not available for direct comparison. Patients treated with any neuroleptic, including aripiprazole, should be closely monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, and weakness). The condition of patients with diabetes mellitus or risk factors for developing diabetes should be regularly monitored for increased glucose levels (see section "Adverse reactions").

Hypersensitivity

Hypersensitivity reactions characterized by allergic symptoms may occur with aripiprazole (see section "Adverse reactions").

Weight gain

Weight gain is frequently observed in patients with schizophrenia or bipolar mania due to comorbid conditions, use of other weight-gain-inducing neuroleptics, and unhealthy lifestyle, which may lead to serious complications. Weight gain has been reported in the post-marketing period in patients treated with aripiprazole. These patients had significant risk factors, such as a history of diabetes mellitus, thyroid disorders, or pituitary adenoma.

Clinical studies have not shown that aripiprazole causes clinically significant weight gain in adults (see section "Pharmacological properties"). However, in adolescent patients with bipolar mania, a relationship between aripiprazole use and weight gain was observed after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section "Adverse reactions").

Dysphagia

Neuroleptics, including aripiprazole, may impair esophageal motility and cause aspiration. Aripiprazole 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. Hypersexuality, compulsive shopping, binge eating, or uncontrolled food cravings, and other impulse and compulsive behaviour disorders have also been reported. It is important that patients and caregivers inform the physician if any of these disorders develop during treatment with aripiprazole. Impulse control disorders may be related to the underlying condition, but in some cases, pathological urges have resolved after 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 (see section "Adverse reactions").

Patients with comorbid attention deficit hyperactivity disorder (ADHD)

Despite the high prevalence of ADHD in bipolar I disorder, safety data on concomitant use of aripiprazole and stimulants are limited; therefore, caution should be exercised when using Frame®.

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").

Lactose

It should be noted that the medicinal product Frame® contains lactose:

Frame® 5 mg (1 tablet) contains 47.53 mg of lactose monohydrate.

Frame® 10 mg (1 tablet) contains 95.05 mg of lactose monohydrate.

Frame® 15 mg (1 tablet) contains 142.58 mg of lactose monohydrate.

Frame® 30 mg (1 tablet) contains 285.15 mg of lactose monohydrate.

Therefore, this medicinal product should not be administered to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

The product contains aspartame, a phenylalanine derivative, which may be hazardous for patients with phenylketonuria.

Use during pregnancy or breastfeeding

Pregnancy

Adequate and well-controlled studies on the use of aripiprazole in pregnant women have not been conducted. Congenital anomalies have been reported, but a causal relationship has not been established. Available animal data do not allow exclusion of embryofetotoxic potential. Patients should consult their physician if pregnancy occurs or is planned during aripiprazole treatment. Due to insufficient safety data during pregnancy, the medicinal product should be prescribed only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus. Use of neuroleptics, including aripiprazole, during the third trimester of pregnancy may result in adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome of varying severity and duration. Agitation, hypertonia or hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, newborns should be carefully monitored.

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 influence reaction speed when driving or operating machinery

Aripiprazole may have a moderate or minor effect on the ability to drive or operate machinery due to nervous system and visual side effects such as sedation, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions").

Method of administration and dosage.

The tablets should be taken orally.

Adults

Schizophrenia. The recommended initial dose of the medicinal product is 10 or 15 mg once daily, regardless of food intake. The maintenance dose is 15 mg daily. The effective dose range of the medicinal product is 10 to 30 mg daily. Increased efficacy of the drug at doses above 15 mg has not been demonstrated, although some patients may require higher doses. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder. The recommended initial dose is 15 mg once daily, regardless of food intake, both as monotherapy and in combination therapy. Some patients may require a higher dose. The maximum daily dose should not exceed 30 mg.

Prevention of recurrent manic episodes in bipolar I disorder. For prevention of manic episodes in patients previously treated with aripiprazole as monotherapy or in combination therapy, treatment should be continued at the same doses.

The need for dose adjustment or dose reduction is determined by the physician, taking into account the patient's clinical condition.

Children

Schizophrenia in adolescents aged 15 years and older: the recommended dose of the medicinal product Fraym® 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 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"). Fraym® is effective in the dose range of 10 mg/day to 30 mg/day. Increased efficacy at doses higher than 10 mg daily has not been demonstrated, although individual patients may benefit from higher doses.

Fraym® is not recommended for patients with schizophrenia under the age of 15 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 the medicinal product Fraym® 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 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 daily has not been demonstrated, and at a daily dose of 30 mg, the frequency of significant adverse reactions, including extrapyramidal symptoms, somnolence, fatigue, and weight gain, was substantially increased (see section "Side effects"). Therefore, doses above 10 mg/day should be used only in exceptional cases and with 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, Fraym® is not recommended for patients under 13 years of age (see sections "Side effects" and "Pharmacological properties").

Special patient groups

Patients with hepatic impairment

Dose adjustment is not required for patients with mild to moderate hepatic impairment. There are insufficient data to provide recommendations for patients with severe hepatic impairment. Dose selection in such patients should be done with extreme caution. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.

Patients with renal impairment

Dose adjustment is not required.

Elderly patients

The safety and efficacy of aripiprazole in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older have not been studied. Due to the increased sensitivity of this patient group, a lower initial dose should be considered if clinical factors so require (see section "Special precautions").

Gender

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

Smokers

Dose adjustment is not required for smokers due to the metabolic pathway of aripiprazole.

Dose adjustment with concomitant therapy

When aripiprazole is used concomitantly with strong CYP3A4 or CYP2D6 inhibitors, the dose of aripiprazole should be reduced. When such inhibitors are discontinued from combination therapy, the dose of aripiprazole should be increased.

When aripiprazole is used concomitantly with a strong CYP3A4 inducer, the dose of aripiprazole should be increased. When the inducer is discontinued from combination therapy, the dose of aripiprazole should be reduced to the recommended dose.

Children.

Fraym® 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 bipolar I disorder in adolescents aged 13 years and older for up to 12 weeks (see section "Method of administration and dosage"). Treatment should be initiated at a dose of 2 mg (using aripiprazole oral solution 1 mg/mL).

Overdose.

There have been reports of acute aripiprazole overdose in adults due to accidental or intentional single ingestion of up to 1260 mg, without fatal outcome. Medically significant symptoms included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea. In addition, cases of aripiprazole overdose in children (ingestion up to 195 mg) have been described, also without fatal outcome. Potentially dangerous symptoms of overdose include somnolence, transient loss of consciousness, and extrapyramidal symptoms.

Treatment: in case of overdose, supportive therapy is required, including ensuring adequate airway patency, oxygen therapy, mechanical ventilation, and symptomatic treatment. Immediate cardiac monitoring with ECG recording should be initiated to detect arrhythmias. After confirmed or suspected aripiprazole overdose, careful medical observation is required until all symptoms resolve.

Activated charcoal (50 g), administered within 1 hour after aripiprazole intake, reduces the AUC and Cmax of aripiprazole in blood by 51% and 41%, respectively, suggesting potential effectiveness of activated charcoal in overdose management.

Although there are no reliable data on the use of hemodialysis in aripiprazole overdose, a beneficial effect is unlikely due to the extensive plasma protein binding of aripiprazole.

Adverse reactions.

The most commonly reported adverse reactions in placebo-controlled studies were akathisia and nausea — occurring in over 3% of patients receiving oral aripiprazole.

List of adverse reactions.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

The frequency of adverse reactions identified during the post-marketing period cannot be estimated, as they are derived from spontaneous reports, and are therefore classified as frequency not known.

Description of individual adverse reactions

Adults

Extrapyramidal symptoms (EPS)

Schizophrenia: In a 52-week controlled study, the incidence of EPS, including parkinsonism, akathisia, dystonia, and dyskinesia, was lower (25.7%) in patients receiving aripiprazole compared to those 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 12-week controlled 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 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 constriction, difficulty swallowing, breathing difficulties, and/or tongue protrusion. Although these symptoms may occur at low doses, they are more frequent and severe at high doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger patients.

Prolactin

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

Laboratory parameters

The proportion of patients with clinically significant changes in standard laboratory and lipid parameters did not differ substantially between the aripiprazole and placebo groups. Elevated creatine phosphokinase (CPK) levels (mostly transient and asymptomatic) were observed in 3.5% of patients receiving aripiprazole, compared to 2.0% in the placebo group.

Children

Schizophrenia in adolescents aged 15 years and older

In a short-term, placebo-controlled clinical study 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 receiving aripiprazole than in adults (and more frequently than with placebo).

Somnolence/sedation and extrapyramidal disorders were reported very commonly (≥ 1/10), as well as dry mouth, increased appetite, and orthostatic hypotension (≥ 1/100, < 1/10). The safety profile observed in a 26-week open-label study was similar to that observed in the short-term placebo-controlled study.

The safety profile observed 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 (≥ 1/100, < 1/10).

In the pooled group of adolescents with schizophrenia aged 13–17 years treated with aripiprazole 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 treated with 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, tachycardia, 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 pediatric patients with bipolar disorder compared to those with schizophrenia.

In pediatric patients aged 10–17 years with bipolar disorder treated 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, hypersexuality, compulsive shopping, and compulsive overeating (see section "Special precautions").

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging. No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging. 10 tablets per blister. 3 blisters per pack.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak" (manufacturing from bulk product supplied by the manufacturer Rontis Hellas Medical and Pharmaceutical Products S.A., Greece).

Address of manufacturer and location of business activity.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.