Eridon®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERIDON® (ERIDON)

Composition:

Active substance: risperidone;

1 tablet contains 2 mg or 4 mg of risperidone;

Excipients: lactose monohydrate, microcrystalline cellulose, maize starch, povidone, magnesium stearate, colloidal anhydrous silicon dioxide, sodium lauryl sulfate;

Coating: Opadry Y-1-7000 White (hypromellose, titanium dioxide (E 171), polyethylene glycol), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, capsule-shaped tablets, film-coated.

Pharmacotherapeutic group. Antipsychotics. ATC code N05A X08.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Risperidone is a selective monoaminergic antagonist with unique properties. It exhibits high affinity for serotonergic 5-HT2 and dopaminergic D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against the positive symptoms of schizophrenia, it causes less pronounced motor activity suppression and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect to include negative and affective symptoms of schizophrenia.

Pharmacokinetics.

Risperidone is metabolized to 9-hydroxyrisperidone, which has a similar pharmacological activity to risperidone (see section "Metabolism and elimination").

Absorption

After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1–2 hours; in elderly patients, peak concentrations are reached within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). Relative bioavailability after oral administration of risperidone in tablet form is 94% (CV = 10%) compared to administration as a solution. Food does not affect drug absorption; therefore, risperidone can be administered regardless of food intake. Absolute bioavailability is 66% in fast metabolizers and 82% in slow metabolizers.

Distribution

Risperidone is rapidly distributed throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and acidic α1-glycoprotein. Risperidone is 90% bound to plasma proteins; 9-hydroxyrisperidone is 77% bound. Steady-state concentrations of risperidone in the body are achieved within 1 day in most patients. Steady-state concentrations of 9-hydroxyrisperidone are achieved within 4–5 days.

Metabolism and elimination

Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which exerts pharmacological effects similar to risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. Cytochrome CYP2D6 is subject to genetic polymorphism. In fast metabolizers of CYP2D6, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, this conversion occurs much more slowly. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in fast metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both fast and slow metabolizers of cytochrome CYP2D6.

Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. One week after drug administration, 70% of the dose is excreted in urine and 14% in feces. The concentration of risperidone and 9-hydroxyrisperidone in urine accounts for 35–45% of the administered dose. The remainder consists of inactive metabolites. After oral administration in patients with psychosis, the elimination half-life is approximately 3 hours. The elimination half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, it is 34 hours.

Linearity

Plasma concentrations of risperidone are proportional to the administered dose (within the therapeutic dose range).

Elderly patients and patients with renal or hepatic impairment

A pharmacokinetic study of single-dose administration in elderly patients demonstrated that in these patients, the plasma concentration of the active antipsychotic fraction is 43% higher, the elimination half-life is 38% longer, and the clearance of the active antipsychotic fraction is 30% lower.

In adult patients with impaired renal function, the clearance of the active fraction was ~48% of that in adults with normal renal function. In adult patients with severe renal impairment, clearance was ~31% of that in adults with normal renal function. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (approximately 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in young adults). In patients with hepatic insufficiency, normal plasma concentrations of risperidone were observed, but the mean value of the free fraction of risperidone in plasma was increased by 37.1%.

After oral administration, the clearance and elimination half-life of risperidone and the active antipsychotic fraction in patients with moderate to severe hepatic impairment did not differ significantly from those in young healthy volunteers.

Children

The pharmacokinetics of risperidone, 9-hydroxyrisperidone, and the active antipsychotic fraction in children are similar to those in adults.

Gender, race, and smoking

Population pharmacokinetic analysis did not reveal any significant influence of gender, race, or smoking on the pharmacokinetics of risperidone or the active antipsychotic fraction.

Clinical characteristics.

Indications.

• Treatment of schizophrenia;
• treatment of moderate to severe manic episodes in bipolar disorders;
• short-term treatment (up to 6 weeks) of marked aggression in patients with moderate to severe Alzheimer's type dementia when there is a threat of harm to self or others and lack of response to non-pharmacological treatment methods (see sections "Special instructions" and "Dosage and administration");
• symptomatic short-term treatment (up to 6 weeks) of marked aggression in behavioral disorders in children aged 5 years and adolescents with below-average intellectual development or intellectual disability diagnosed according to DSM-IV criteria, where the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological treatment should be an integral part of a comprehensive treatment program including psychological support and educational interventions. It is recommended that risperidone be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or a physician experienced in managing behavioral disorders in children and adolescents.

Contraindications.

Hypersensitivity to the active ingredient or to any excipient of the medicinal product.

Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances).

Dementia and suspected dementia with Lewy bodies (at least 2 of the following symptoms in addition to dementia: parkinsonism, visual hallucinations, fluctuating gait).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interaction

Medicinal products that prolong the QT interval

As with other antipsychotics, caution should be exercised when prescribing risperidone with medicinal products that prolong the QT interval, for example, antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, some antimalarials (quinine, mefloquine), and products causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or medicinal products that inhibit hepatic metabolism of risperidone. This list is indicative and incomplete.

Central-acting agents and alcohol

Risperidone should be used with caution in combination with other centrally acting substances, including alcohol, opioids, antihistamines, and benzodiazepines, due to an increased risk of sedation.

Levodopa and dopamine agonists

Risperidone may exhibit antagonistic effects to levodopa and other dopamine agonists. If such a combination is considered necessary, especially in the terminal stage of Parkinson's disease, the lowest effective doses of each drug should be prescribed.

Medicinal products with hypotensive effect

Clinically significant arterial hypotension has been observed during the post-marketing period with concomitant use of risperidone and antihypertensive medicinal products.

Psychostimulants

Use of risperidone in combination with psychostimulants (e.g., methylphenidate) may lead to the emergence of extrapyramidal symptoms after dose adjustment of one or both agents (see section "Special instructions").

Paliperidone

Concomitant use of oral risperidone with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone and their combination may lead to an additive effect of the active antipsychotic fraction.

Pharmacokinetic interactions

Food does not affect the absorption of risperidone.

Risperidone is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or potent inhibitors or inducers of CYP3A4 and/or P-gp activity, may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.

Potent CYP2D6 inhibitors

Concomitant use of risperidone with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but to a lesser extent than the concentration of the active antipsychotic fraction. Higher doses of a potent CYP2D6 inhibitor may increase the concentration of the active antipsychotic fraction of risperidone (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are expected to affect plasma concentrations of risperidone similarly. At the start of concomitant therapy, and upon discontinuation of paroxetine, quinidine, or another potent CYP2D6 inhibitor, especially at high doses, the physician should review the risperidone dose.

Inhibitors of CYP3A4 and P-glycoprotein

Concomitant use of risperidone with potent inhibitors of CYP3A4 and/or P-glycoprotein may significantly increase plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation of concomitant therapy, and upon discontinuation of itraconazole or other potent inhibitors of CYP3A4 and/or P-glycoprotein, the physician should review the risperidone dose.

Inducers of CYP3A4 and P-glycoprotein

Concomitant use of risperidone with potent inducers of CYP3A4 and/or P-glycoprotein may reduce plasma concentrations of the active antipsychotic fraction of risperidone. At the start of therapy, and upon discontinuation of carbamazepine or other potent inducers of CYP3A4/P-glycoprotein, the physician should review the risperidone dose. The effect of CYP3A4 inducers depends on time, with maximum impact reached at least 2 weeks after initiation of treatment. Accordingly, after discontinuation, induction of CYP3A4 may persist for at least 2 weeks.

Medicinal products with high protein binding

When risperidone is used concomitantly with other medicinal products that are highly bound to plasma proteins, clinically significant displacement of either drug from the protein fraction has not been observed. When used concomitantly with such a medicinal product, the prescribing information of that product should be consulted regarding metabolic pathways and the need for dose adjustment.

Children

Interaction studies have been conducted only in adult patients. It is unknown whether the results obtained can be applied to children.

Concomitant use of psychostimulants (e.g., methylphenidate) with risperidone in children and adolescents did not affect the pharmacokinetics or efficacy of risperidone.

Effect of other medicinal products on the pharmacokinetics of risperidone

Antibacterial medicinal products

• Erythromycin, a moderate inhibitor of CYP3A4 and an inhibitor of P-glycoprotein, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
• Rifampicin, a potent inducer of CYP3A4 and an inducer of P-glycoprotein, reduces plasma concentrations of the active antipsychotic fraction.

Cholinesterase inhibitors

• Donepezil and galantamine, substrates of CYP2D6 and CYP3A4, do not demonstrate clinically significant effects on the pharmacokinetics of risperidone or the active antipsychotic fraction.

Antiepileptic medicinal products

• Carbamazepine, a potent inducer of CYP3A4 and an inducer of P-glycoprotein, has been shown to reduce plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may be observed with phenytoin and phenobarbital, which are also inducers of hepatic enzymes CYP3A4 and P-glycoprotein.
• Topiramate moderately reduces the bioavailability of risperidone and does not affect the bioavailability of the active antipsychotic fraction. It is unlikely that this interaction may cause a clinically significant effect.

Antifungal medicinal products

• Itraconazole, a potent inhibitor of CYP3A4 and an inhibitor of P-glycoprotein, at a dose of 200 mg per day, increases plasma concentrations of the active antipsychotic fraction by approximately 70% when used concomitantly with risperidone at doses of 2 to 8 mg per day.
• Ketoconazole, a potent inhibitor of CYP3A4 and an inhibitor of P-glycoprotein, at a dose of 200 mg per day, increases plasma concentrations of risperidone and decreases concentrations of 9-hydroxyrisperidone.

Antipsychotic medicinal products

• Phenothiazines may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction.

Antiviral medicinal products

• Protease inhibitors: study data are lacking; since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and ritonavir-boosted protease inhibitors may increase plasma concentrations of the active antipsychotic fraction of risperidone.

Beta-blockers

• Some beta-blockers may increase plasma concentrations of risperidone, but do not affect plasma concentrations of the active antipsychotic fraction.

Calcium channel blockers

• Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-glycoprotein, increases plasma concentrations of risperidone and the active antipsychotic fraction.

Medicinal products for gastrointestinal disorders

• H2-receptor antagonists: cimetidine and ranitidine, weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone and minimally affect the bioavailability of the active antipsychotic fraction.

SSRIs and tricyclic antidepressants

• Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but to a lesser extent than the concentration of the active antipsychotic fraction.
• Paroxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but (at doses up to 20 mg per day) to a lesser extent than the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction.
• Tricyclic antidepressants may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
• Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at doses up to 100 mg per day, do not cause clinically significant changes in plasma concentrations of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg per day may increase plasma concentrations of the active antipsychotic fraction of risperidone.

Effect of risperidone on the pharmacokinetics of other medicinal products

Antiepileptic medicinal products

• Risperidone has no clinically significant effect on the pharmacokinetics of valproate or topiramate.

Antipsychotic medicinal products

• Aripiprazole, a substrate of CYP2D6 and CYP3A4: oral or injectable formulations of risperidone do not affect the pharmacokinetics of aripiprazole or its active metabolite dehydroaripiprazole.

Cardiac glycosides

• Risperidone has no clinically significant effect on the pharmacokinetics of digoxin.

Lithium

• Risperidone has no clinically significant effect on the pharmacokinetics of lithium.

Concomitant use of risperidone with furosemide

See section "Special instructions" regarding increased mortality in elderly patients with dementia when used concomitantly with furosemide.

Special precautions for use.

Geriatric patients with dementia

Increased mortality

An increased mortality rate has been observed in elderly patients with dementia treated with atypical antipsychotic drugs compared to those in the placebo group, based on a meta-analysis of 17 controlled studies of atypical antipsychotics, including risperidone. In a placebo-controlled trial using risperidone in this patient population, the incidence of mortality was 4.0% compared to 3.1% in the placebo group. The odds ratio (95% confidence interval) was 1.21 (0.7; 2.1). The mean age of patients who died was 86 years (range: 67–100 years).

Data from two large observational studies indicate that elderly patients with dementia treated with conventional (typical) antipsychotics have a slightly higher risk of death compared to patients not receiving antipsychotics. Based on available data, the exact level of this risk cannot be determined, and the cause of the increased risk is unknown. The extent to which these observations of increased mortality risk are attributable to antipsychotic drug use, as opposed to individual patient characteristics, is unclear.

Concomitant use with furosemide

In a placebo-controlled study in elderly patients with dementia, an increased mortality rate was observed when risperidone was used concomitantly with furosemide (7.3%; mean age: 89 years, range: 75–97 years) compared to patients treated with risperidone alone (3.1%; mean age: 84 years, range: 70–96 years) or furosemide alone (4.1%; mean age: 80 years, range: 67–90 years). Increased mortality among patients treated with both risperidone and furosemide was observed in 2 out of 4 clinical trials. No increased mortality rate was observed among patients who used risperidone concomitantly with other diuretics (mainly low-dose thiazide diuretics).

The pathophysiological mechanisms underlying this observation have not been established. The cause of death was also not uniform. However, particular caution should be exercised when prescribing the drug in such cases, and the risks and benefits of this combination or combinations with other potential diuretics should be evaluated before administration. No increased mortality was observed among patients who received risperidone with other diuretics. Regardless of treatment, dehydration was a common risk factor for mortality and should be carefully monitored in patients with dementia.

Cerebrovascular adverse reactions

It is known that in placebo-controlled clinical trials, elderly patients with dementia treated with risperidone experienced a higher incidence (approximately 3 times higher) of cerebrovascular adverse events (strokes and transient ischemic attacks), often fatal, compared to those receiving placebo (mean age: 85 years; range: 73–97 years).

Pooled data from 6 placebo-controlled trials involving elderly patients with dementia (aged 65 years and older) demonstrated cerebrovascular disorders (serious and non-serious, combined) in 3.3% (33/1009) of patients treated with risperidone compared to 1.2% (8/712) of patients receiving placebo. The odds ratio (95% CI) between the risperidone and placebo groups was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk of cerebrovascular adverse events cannot be ruled out for other antipsychotics or other patient groups. Risperidone should be used with caution in patients with risk factors for stroke.

The risk of cerebrovascular adverse reactions is significantly higher in patients with mixed or vascular dementia compared to Alzheimer's dementia. Therefore, risperidone should not be prescribed to patients with dementia types other than Alzheimer's dementia.

The risks and benefits of prescribing risperidone to elderly patients with dementia, particularly the risk of stroke, should be carefully weighed. Patients and caregivers should be instructed to immediately report signs of possible cerebrovascular events, such as sudden weakness, facial, arm, or leg numbness, or speech and vision disturbances. All treatment options, including discontinuation of risperidone therapy, should be promptly considered.

For persistent aggression in patients with moderate to severe Alzheimer's disease, risperidone should be prescribed only for short-term use as an adjunct to non-pharmacological interventions that have shown limited or no efficacy, provided there is no potential risk of harm to self or others.

During treatment, patients should be regularly assessed, and the need for continued therapy should be re-evaluated.

Orthostatic hypotension

Due to the α1-blocking activity of risperidone, particularly at the beginning of treatment, orthostatic hypotension may occur. Clinically significant hypotension has been observed in the post-marketing period with concomitant use of risperidone and antihypertensive agents. Risperidone should be used with caution in patients with cardiovascular disorders (heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disorders). In such cases, dosage should be gradually adjusted (see section "Dosage and administration"). If hypotension occurs, dose reduction should be considered.

Leukopenia, neutropenia, agranulocytosis

Cases of leukopenia, neutropenia, and agranulocytosis have been reported during treatment with antipsychotic agents, including risperidone. Agranulocytosis has been reported very rarely (<1/10,000 patients) in the post-marketing period.

Patients with a history of significant leukocyte reduction or drug-induced leukopenia/neutropenia should be closely monitored during the first few months of treatment, and risperidone should be discontinued if signs of significant leukocyte reduction occur and no other causes are identified.

Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. In cases of severe neutropenia (<1×10⁹/L), risperidone treatment should be discontinued, and leukocyte counts should be monitored until recovery.

Tardive dyskinesia/extrapyramidal symptoms

Tardive dyskinesia, characterized by involuntary rhythmic movements (mainly of the tongue and/or face), has been reported with drugs possessing dopamine receptor antagonist properties. The occurrence of extrapyramidal symptoms is a risk factor for developing tardive dyskinesia. If signs or symptoms of tardive dyskinesia occur, discontinuation of all antipsychotic drugs should be considered. Caution is advised when using psychostimulants (e.g., methylphenidate) concomitantly with risperidone, as extrapyramidal symptoms may occur when adjusting the dose of either or both drugs. Gradual discontinuation of psychostimulants is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neuroleptic malignant syndrome

Cases of neuroleptic malignant syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated creatine phosphokinase levels, have been rarely reported with classical neuroleptic agents. Additional features include myoglobinuria (rhabdomyolysis) and acute renal failure. If neuroleptic malignant syndrome develops, all antipsychotic drugs, including risperidone, should be discontinued.

Parkinson's disease and dementia with Lewy bodies

Physicians should carefully weigh the risks and benefits when prescribing antipsychotics, including risperidone, to patients with Parkinson's disease or dementia with Lewy bodies. Risperidone use may worsen the course of Parkinson's disease. Patients with either of these conditions may have an increased risk of neuroleptic malignant syndrome and heightened sensitivity to antipsychotics (e.g., confusion, reduced pain sensitivity, postural instability with frequent falls, in addition to extrapyramidal symptoms).

Hyperglycemia and diabetes mellitus

Hyperglycemia, diabetes mellitus, or exacerbation of existing diabetes has been reported during risperidone treatment. In some cases, pre-existing obesity was noted as a potential contributing factor. Very rarely, ketoacidosis and rarely, diabetic coma, have been reported. Appropriate clinical monitoring according to antipsychotic use guidelines is recommended. Patients receiving any atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should be regularly evaluated for worsening glucose control.

Weight gain

Significant weight gain has been reported with risperidone use. Weight monitoring is recommended.

Hyperprolactinemia

Hyperprolactinemia is a common adverse effect of risperidone treatment. Patients with adverse effects potentially related to elevated plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility impairment, decreased libido, erectile dysfunction, galactorrhea) should have their prolactin levels monitored.

Tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although a clear association with antipsychotic use has not been established in clinical and epidemiological studies, risperidone should be prescribed with caution in patients with relevant medical history. Risperidone should be used cautiously in patients with hyperprolactinemia and prolactin-dependent tumors.

QT interval prolongation

Very rare cases of QT interval prolongation have been reported in the post-marketing period. Risperidone, like other antipsychotics, should be used with caution in patients with known cardiovascular disorders, bradycardia, electrolyte imbalances (hypokalemia, hypomagnesemia), or a family history of QT prolongation, as this may increase the risk of arrhythmogenic effects. Precautions are also required when risperidone is used concomitantly with other drugs that prolong the QT interval.

Seizures

Risperidone should be used with caution in patients with a history of seizures or other conditions that may potentially lower the seizure threshold.

Priapism

Priapism may occur during risperidone treatment due to its alpha-adrenergic blocking effect.

Body temperature regulation

Antipsychotic drugs may impair the body's ability to reduce core body temperature. Appropriate care is recommended for patients receiving risperidone who may be exposed to conditions that can elevate core body temperature: intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic drugs, or dehydration.

Antiemetic effect

An antiemetic effect of risperidone was observed in preclinical studies. This property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, or brain tumors.

Liver and kidney function impairment

Patients with impaired kidney function have a reduced ability to eliminate the active antipsychotic fraction of the drug compared to adults with normal kidney function. In patients with impaired liver function, increased plasma concentrations of the free fraction of risperidone are observed (see section "Dosage and administration").

Thromboembolism

Cases of venous thromboembolism have been reported with antipsychotic drug use. Since patients treated with antipsychotics often have acquired risk factors for venous thromboembolism, all potential risk factors for thromboembolism should be identified before and during risperidone treatment, and appropriate preventive measures should be taken.

Intraoperative floppy iris syndrome (IFIS)

Intraoperative floppy iris syndrome has been observed during cataract surgery in patients treated with α1-adrenergic receptor antagonists, including risperidone.

IFIS may increase the risk of ocular complications during and after surgery. The ophthalmic surgeon should be informed about past or current use of antipsychotic drugs. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risk of discontinuing antipsychotic treatment should be weighed.

Children

The risk-benefit ratio should be carefully evaluated before prescribing risperidone to children or adolescents with behavioral disorders, and physical and social causes of aggressive behavior (e.g., pain stimuli or inappropriate response to environment) should be assessed. The sedative effect of risperidone should be closely monitored in pediatric patients due to potential effects on learning ability. Adjusting the timing of risperidone administration may improve the impact of sedation on children's and adolescents' ability to concentrate.

Risperidone use has been associated with minor increases in body weight and body mass index (BMI). Baseline weight measurement is recommended before starting treatment, and regular weight monitoring is advised during therapy. Growth changes observed in long-term open-label extension studies were within expected age-related norms. The effect of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.

Due to the potential impact of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including measurement of height, weight, assessment of sexual maturation, menstrual cycle, and other prolactin-dependent phenomena, should be considered.

Results from a small post-marketing observational study showed that patients aged 8–16 years receiving risperidone were on average 3.0–4.8 cm taller than those receiving other antipsychotics. However, data from this study are insufficient to determine whether risperidone affects final adult height, whether the measurement results are directly related to risperidone's effect on bone growth, whether the underlying disease affects bone growth, or whether this is a result of better disease control leading to greater height gain.

Extrapyramidal symptoms and other movement disorders should be regularly monitored during risperidone treatment.

Dosage recommendations for children are provided in the section "Dosage and administration."

Excipients

This medicinal product contains lactose. If intolerance to certain sugars is diagnosed, consult a physician before taking this medicinal product.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

Controlled studies in pregnant women have not been conducted. Although teratogenic effects were not observed in animal studies, other forms of reproductive toxicity were noted. The potential risk in humans is unknown.

Newborns whose mothers used antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of developing reversible extrapyramidal symptoms and/or withdrawal syndrome. These symptoms include agitation, abnormally increased or decreased muscle tone, tremor, somnolence, respiratory disorders, or feeding difficulties. These complications may vary in severity, so newborns should be closely monitored.

Risperidone should not be used during pregnancy unless absolutely necessary. If treatment needs to be discontinued during pregnancy, it should not be stopped abruptly.

Breastfeeding period

In animal studies, risperidone and 9-hydroxyrisperidone were found to pass into breast milk. There are observations that risperidone and 9-hydroxyrisperidone may also pass into human breast milk. There are no data on adverse reactions in breastfed infants. Therefore, the benefits of breastfeeding and the potential risk to the infant should be carefully weighed.

Fertility

Like other medicinal products that are dopamine D2 receptor antagonists, risperidone increases prolactin levels.

Hyperprolactinemia may suppress gonadotropin-releasing hormone production in the hypothalamus, leading to reduced pituitary gonadotropin secretion. This may negatively affect reproductive function in both women and men due to impaired gonadal steroidogenesis.

No relevant effects were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

Risperidone may have 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 (see section "Adverse reactions"). During treatment, patients are advised to refrain from driving or operating machinery until their individual sensitivity to the drug is known.

Method of Administration and Dosage

To achieve a dose of 0.25–1.5 mg, risperidone oral solution is recommended.

Dosage

Schizophrenia

Adults

Risperidone may be administered once or twice daily.

Treatment should be initiated at 2 mg of risperidone per day; on the second day, the dose may be increased to 4 mg. Thereafter, the dose may be maintained unchanged or, if necessary, continued individual dose adjustment may be performed. The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or a reduced initial and maintenance dose.

Doses exceeding 10 mg of risperidone per day have not demonstrated higher efficacy compared to lower doses, but may cause extrapyramidal symptoms. The safety of doses above 16 mg per day has not been studied; therefore, such doses must not be used.

Elderly patients (aged 65 years and older)

The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily by increments of 0.5 mg twice daily.

Children

The use of the drug in children (under 18 years of age) with schizophrenia is not recommended due to lack of efficacy data.

Manic episodes in bipolar disorders

Adults

The recommended initial dose of risperidone is 2 mg once daily in the evening. The dose may be individually increased by adding 1 mg/day no more frequently than every 24 hours. The recommended dose range is 1–6 mg per day to optimize efficacy and tolerability for each patient. The use of risperidone at doses exceeding 6 mg per day in patients with manic episodes has not been studied.

As with other forms of symptomatic treatment, during long-term use of risperidone, the dose should be periodically reviewed and adjusted throughout the course of therapy.

Elderly patients (aged 65 years and older)

The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily by increments of 0.5 mg twice daily. Since experience with the use of the drug in elderly patients is limited, caution is recommended.

Children

The use of the drug in children (under 18 years of age) with bipolar mania is not recommended due to lack of efficacy data.

Short-term treatment of severe aggression in patients with Alzheimer's type dementia

The recommended initial dose is 0.25 mg twice daily. Risperidone oral solution is the recommended dosage form for a 0.25 mg dose. If necessary, the dose may be increased by increments of 0.25 mg twice daily no more frequently than every other day. For most patients, the optimal dose is 0.5 mg twice daily. However, for some patients, an effective dose is 1 mg twice daily.

Risperidone should not be used for longer than 6 weeks in patients with severe aggression due to Alzheimer's disease. As with other forms of symptomatic treatment, the use of risperidone should be periodically reviewed and adjusted throughout the course of therapy.

Short-term symptomatic treatment (up to 6 weeks) of severe aggression in behavioral disorders

Children and adolescents aged 5 to 18 years

Patients with body weight ≥ 50 kg

The recommended initial dose is 0.5 mg once daily. If necessary, the dose should be adjusted by adding 0.5 mg once daily no more frequently than every other day. The optimal dose for most patients is 1 mg once daily. However, for some patients, a positive effect may be achieved with no more than 0.5 mg once daily, while others may require 1.5 mg once daily.

Patients with body weight < 50 kg

The recommended initial dose is 0.25 mg once daily. Risperidone oral solution is the recommended dosage form for a 0.25 mg dose. If necessary, the dose may be adjusted by adding 0.25 mg once daily no more frequently than every other day. The optimal dose for most patients is 0.5 mg once daily. However, for some patients, no more than 0.25 mg once daily may be sufficient to achieve a positive effect, while others may require 0.75 mg once daily.

As with other forms of symptomatic treatment, the use of risperidone should be periodically reviewed and adjusted throughout the course of therapy.

Children

The use of the drug in children under 5 years of age is not recommended due to lack of experience with risperidone for the treatment of behavioral disorders in this age group.

Patients with hepatic and renal impairment

In patients with impaired renal function, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with impaired hepatic function, the plasma concentration of the free fraction of risperidone is increased.

Regardless of the indication, these patients should be prescribed half the initial and maintenance dose, and dose titration should be slower.

Risperidone should be used with caution in this patient population.

Method of administration

Risperidone is intended for oral administration. Food intake does not affect the absorption of risperidone.

At the end of treatment, gradual discontinuation of the drug is recommended. After abrupt discontinuation of high doses of antipsychotic drugs, isolated cases of acute withdrawal symptoms have been observed, including nausea, vomiting, increased sweating, and insomnia (see section "Adverse reactions"). Relapses of psychotic symptoms may also occur, and cases of involuntary movements (e.g., akathisia, dystonia, and dyskinesia) have been reported.

Switching from therapy with other antipsychotic agents

If clinically justified, it is recommended to gradually discontinue previous antipsychotic therapy when initiating risperidone treatment. If a patient is being switched from antipsychotic agents in "depot" form, risperidone therapy should be initiated instead of the next scheduled injection. The need for continuation of current antiparkinsonian therapy should be periodically evaluated.

Children

Risperidone is used for the treatment of severe aggression in behavioral disorders in children aged 5 years and older.

Overdose

Symptoms
Signs and symptoms observed in overdose are the known adverse reactions of the drug, manifested in an intensified form: somnolence and sedation, tachycardia and arterial hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported in cases of overdose. Cases of Torsades de pointes tachycardia associated with risperidone overdose in combination with paroxetine have been reported. In cases of acute overdose, the possibility of ingestion of multiple drugs should be considered.

Treatment
Airway patency should be ensured and maintained to provide adequate ventilation and oxygenation. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal with a laxative should be considered within 1 hour of drug ingestion. Cardiovascular monitoring, including continuous electrocardiogram (ECG) recording to detect possible arrhythmias, is indicated. Risperidone has no specific antidote; therefore, appropriate supportive measures should be taken. In cases of acute overdose, potential drug interactions involving multiple agents should be analyzed. Arterial hypotension and vascular collapse should be treated with measures such as intravenous infusions and/or sympathomimetic agents. In case of acute extrapyramidal symptoms, anticholinergic agents should be administered. Continuous medical supervision should be maintained until the patient has fully recovered.

Adverse Reactions

The most commonly reported adverse reactions (frequency ≥ 10%) are parkinsonism, sedation/somnolence, headache, and insomnia. Parkinsonism and akathisia are dose-dependent adverse reactions.

The adverse reactions listed below include those reported during clinical trials and in the post-marketing period. Frequency of adverse reactions: 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), and frequency not known (cannot be estimated from available data).

Within each category, adverse reactions are listed in order of decreasing severity.

Infections and infestations: common – pneumonia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, ear infections, influenza; uncommon – respiratory tract infections, cystitis, eye infections, tonsillitis, onychomycosis, localized subcutaneous tissue infection, viral infection, acrodermatitis; rare – infection.

Blood and lymphatic system disorders: uncommon – neutropenia, decreased leukocyte count, thrombocytopenia, anemia, decreased hematocrit, increased eosinophil count; rare – agranulocytosis.

Immune system disorders: uncommon – hypersensitivity; rare – anaphylactic reaction.

Endocrine disorders: common – hyperprolactinemia; rare – impaired antidiuretic hormone secretion, glucosuria.

Metabolism and nutrition disorders: common – weight gain, increased appetite, decreased appetite; uncommon – diabetes mellitus^b, hyperglycemia, polydipsia, weight loss, anorexia, increased cholesterol levels; rare – water intoxication, hypoglycemia, hyperinsulinemia, increased blood triglycerides; very rare – diabetic ketoacidosis.

Psychiatric disorders: very common – insomnia^d; common – sleep disorders, agitation, depression, anxiety; uncommon – mania, confusion, decreased libido, restlessness, night terrors; rare – catatonia, somnambulism, sleep-related eating disorders, blunted affect, anorgasmia.

Nervous system disorders: very common – sedation/somnolence, parkinsonism^d, headache; common – akathisia^d, dystonia^d, dizziness, dyskinesia^d, tremor; uncommon – tardive dyskinesia, cerebral ischemia, unresponsiveness, loss of consciousness, depressed level of consciousness, seizures^d, syncope, psychomotor hyperactivity, balance disorders, coordination disturbances, postural dizziness, attention disturbances, dysarthria, taste disturbances, hypoesthesia, paresthesia; rare – neuroleptic malignant syndrome, cerebrovascular disorders, diabetic coma, rhythmic head bobbing.

Eye disorders: common – blurred vision, conjunctivitis; uncommon – photophobia, dry eyes, increased lacrimation, eye redness; rare – glaucoma, ocular motility disorders, rotatory nystagmus, eyelid crusting, intraoperative floppy-iris syndrome.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus, ear pain.

Cardiac disorders: common – tachycardia; uncommon – atrial fibrillation, atrioventricular block, cardiac conduction disorders, QT interval prolongation on electrocardiogram, bradycardia, ECG abnormalities, palpitations; rare – sinus arrhythmia.

Vascular disorders: common – arterial hypertension; uncommon – arterial hypotension, orthostatic hypotension, flushing; rare – pulmonary embolism, venous thrombosis.

Respiratory, thoracic and mediastinal disorders: common – dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion; uncommon – aspiration pneumonia, pulmonary congestion, worsening airway patency, wheezing, stridor, dysphonia, respiratory disorders; rare – sleep apnea syndrome, hyperventilation.

Gastrointestinal disorders: common – abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache; uncommon – fecal incontinence, fecaloma, gastroenteritis, dysphagia, abdominal distension; rare – pancreatitis, gastrointestinal obstruction, tongue swelling, cheilitis; very rare – intestinal obstruction.

Hepatobiliary disorders: uncommon – increased transaminase levels, increased gamma-glutamyltransferase levels, increased liver enzyme levels; rare – jaundice.

Skin and subcutaneous tissue disorders: common – rash, erythema; uncommon – urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discoloration, acne, seborrheic dermatitis, skin disorders, skin injury; rare – drug eruption, dandruff; very rare – angioedema; frequency not known – Stevens-Johnson syndrome/toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: common – muscle spasms, musculoskeletal pain, back pain, arthralgia; uncommon – increased creatine phosphokinase levels, abnormal posture, joint stiffness, joint swelling, muscle weakness, neck pain; rare – rhabdomyolysis.

Renal and urinary disorders: common – urinary incontinence; uncommon – polyuria, urinary retention, dysuria.

Pregnancy, puerperium and perinatal conditions: rare – drug withdrawal syndrome in newborns.

Reproductive system and breast disorders: uncommon – erectile dysfunction, ejaculation disorder, amenorrhea, menstrual disorders^d, gynecomastia, galactorrhea, sexual dysfunction, breast pain, breast discomfort, vaginal discharge; rare – priapism, menstrual delay, breast engorgement, breast enlargement, nipple discharge.

General disorders and administration site conditions: common – edema^d, pyrexia, chest pain, asthenia, fatigue, pain; uncommon – facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, feeling of warmth, discomfort; rare – hypothermia, decreased body temperature, cold extremities, drug withdrawal syndrome, induration.

Injury, poisoning and procedural complications: common – falls; uncommon – post-surgical pain.

a Hyperprolactinemia in some cases may lead to gynecomastia, menstrual disorders, amenorrhea, anovulation, galactorrhea, impaired fertility, decreased libido, erectile dysfunction.

b Diabetes mellitus was reported in 0.18% of patients receiving risperidone versus 0.11% in the placebo group in placebo-controlled studies. The overall incidence across all clinical trials was 0.43% in patients taking risperidone.

c Not observed in clinical studies of risperidone but identified during post-marketing surveillance.

d Extrapyramidal disorders include: parkinsonism (hypersalivation, muscle rigidity, parkinsonism, sialorrhea, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like face, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (muscle twitching, choreoathetosis, athetosis, myoclonus), dystonia.

Dystonia includes arterial hypertension, torticollis, involuntary muscle contractions, myogenic contractures, blepharospasm, eye movement disorders, tongue paralysis, facial tics, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, trismus. A broader list of symptoms is included, not all of which necessarily have extrapyramidal origin. Insomnia includes difficulty falling asleep, intrasomnic disturbances. Seizures include generalized tonic-clonic seizures. Menstrual disorders include irregular menstruation, oligomenorrhea. Edema includes generalized edema, peripheral edema, pitting edema.

Adverse reactions of paliperidone

Paliperidone is the active metabolite of risperidone; therefore, the adverse reaction profiles of these substances (including oral and injectable formulations) are similar. In addition to the adverse reactions listed above, postural orthostatic tachycardia syndrome has been reported with paliperidone and may also occur with risperidone.

Adverse reactions associated with antipsychotic medicinal products

QT interval prolongation

As with other antipsychotics, QT interval prolongation has been reported during post-marketing use of risperidone. Other cardiac adverse reactions associated with QT prolongation have also been reported with antipsychotics, including ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden cardiac death, cardiac arrest, and Torsades de Pointes.

Venous thromboembolism

Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported during treatment with antipsychotic agents.

Weight gain

Comparison of the number of patients treated with risperidone versus placebo showing ≥ 7% body weight gain in placebo-controlled trials lasting 6 to 8 weeks showed a statistically significant difference in the frequency of weight gain in the risperidone group (18%) compared to the placebo group (9%). In 3-week placebo-controlled trials in adults with acute mania, the frequency of ≥ 7% weight gain was comparable between the risperidone group (2.5%) and placebo group (2.4%), and slightly higher in the active control group (3.5%).

In pediatric populations with behavioral disorders, body weight increased on average by 7.3 kg after 12 months of treatment in long-term studies. Expected annual weight gain for children aged 5–12 years with normal body weight is 3–5 kg. From age 12 onward, annual weight gain remains 3–5 kg for girls, while boys gain on average 5 kg per year.

Additional information on specific patient categories

Adverse reactions reported more frequently in elderly patients with dementia or in children compared to adults are described below.

Elderly patients with dementia

Transient ischemic attack and cerebrovascular disorders were reported during clinical trials with frequencies of 1.4% and 1.5%, respectively, in elderly patients with dementia. Other adverse reactions reported with a frequency ≥ 5% in elderly patients with dementia and at least twice as high as in other adult patient groups: urinary tract infections, peripheral edema, lethargy, and cough.

Children

Overall, the expected adverse reactions in children are similar to those in adults in terms of frequency, type, and severity.

Adverse reactions observed in children (aged 5–17 years) with a frequency ≥ 5% and at least twice as high as in adult patients: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhea, and enuresis.

The long-term impact of risperidone treatment on sexual maturation and growth is not fully understood (see section "Special precautions for use").

Reporting suspected adverse reactions

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

In case of adverse reactions or questions regarding the safety and efficacy of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +380442812333.

Shelf life.

4 years.

Storage conditions.

Store in the original packaging out of reach of children at a temperature not exceeding 25°C.

Packaging.

10 tablets in a blister; 3 or 6 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Dexcel Ltd.
Dexcel Ltd.

Manufacturer's address and location of operations.

1 Dexcel St., Or Akiva, 3060000, Israel
1 Dexcel St., Or Akiva, 3060000, Israel.