Risoplept®

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

Composition:

Active ingredient: risperidone;

1 coated tablet contains 2 mg of risperidone;

Excipients: lactose monohydrate; maize starch; microcrystalline cellulose; hypromellose; magnesium stearate; colloidal anhydrous silicon dioxide; sodium lauryl sulfate; titanium dioxide (E 171); talc; propylene glycol; orange-yellow S (E 110).

Pharmaceutical form. Coated tablets.

Main physicochemical properties: light orange, elongated, biconvex, film-coated tablets with inscriptions "Ris" and "2" separated by a division line.

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05AX08.

Pharmacological Properties

Pharmacodynamics

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 relates to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism toward serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.

Pharmacokinetics

Rispolipt® in the form of orally disintegrating tablets and oral solution are bioequivalent to film-coated tablets.

Risperidone is metabolized to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to that of risperidone.

Absorption

After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1–2 hours; in elderly patients, within 2–3 hours. The absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). The relative bioavailability after oral administration of risperidone in tablet form is 94% (CV = 10%) compared to the solution form. Food does not affect drug absorption; therefore, risperidone can be administered independently of meals. Absolute bioavailability is 66% in rapid 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 is bound to albumin and α1-acid 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 reached within 4–5 days.

Biological Transformation and Elimination

Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. Cytochrome CYP2D6 is subject to genetic polymorphism. In rapid metabolizers, risperidone is quickly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, the conversion is much slower. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in rapid 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 rapid 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 half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, 34 hours.

Linearity

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

Elderly patients and patients with renal or hepatic impairment

Pharmacokinetic studies following single-dose administration in elderly patients have demonstrated that such patients have a 43% higher level of the active antipsychotic fraction, a 38% longer elimination half-life, and a 30% lower clearance of the active antipsychotic fraction.

In adult patients with impaired renal function, the clearance of the active fraction was ~48% of that in adults without renal impairment. In adult patients with severe renal impairment, clearance was ~31% of that in adults without renal impairment. 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.

Sex, race, and smoking

Population pharmacokinetic analysis revealed no apparent influence of sex, age, or smoking habit 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 risk of harm to self or others and when there is no response to non-pharmacological treatment methods (see sections "Dosage and administration" and "Special precautions");
• 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 measures. It is recommended that Risperdal® be prescribed by a specialist in child neurology, child and adolescent psychiatry, or by a physician experienced in treating 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 (in addition to dementia symptoms, at least two of the following: parkinsonism, visual hallucinations, postural instability).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Medicinal products that prolong the QT interval.

As with other antipsychotics, caution should be exercised when administering risperidone with medicinal products that prolong the QT interval, such as 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 agents that inhibit hepatic metabolism of risperidone. This list is indicative and not exhaustive.

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.

Risperdal® 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.

During the post-marketing period, cases of clinically significant hypotension have been observed with concomitant use of risperidone and antihypertensive medicinal products.

Psychostimulants.

The 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 precautions").

Paliperidone.

Concomitant use of oral Risperdal® with paliperidone is not recommended, as paliperidone is an active metabolite of risperidone and their combination may result in additive effects of the active antipsychotic fraction.

Pharmacokinetic interactions.

Food does not affect the absorption of Risperdal®.

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 Risperdal® with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but less so 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 strong CYP2D6 inhibitor, especially at high doses, the physician should review the dose of Risperdal®.

Inhibitors of CYP3A4 and P-gp.

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

Inducers of CYP3A4 and P-gp.

Concomitant use of Risperdal® with potent inducers of CYP3A4 and/or P-gp may reduce plasma concentrations of the active antipsychotic fraction of risperidone. At the start of therapy, and upon discontinuation of carbamazepine or other strong inducers of CYP3A4/P-glycoprotein, the physician should review the dose of Risperdal®. The effect of CYP3A4 inducers depends on duration, with maximum impact possibly achieved at least 2 weeks after initiation of treatment. Accordingly, after discontinuation of the inducer, CYP3A4 induction 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 Risperdal® in children did not affect the pharmacokinetics or efficacy of Risperdal®.

Effect of other medicinal products on the pharmacokinetics of risperidone.

Antibacterial agents

• Erythromycin, a moderate CYP3A4 inhibitor and P-gp inhibitor, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
• Rifampicin, a potent CYP3A4 inducer and P-gp inducer, 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 drugs

• Carbamazepine, a potent CYP3A4 inducer and P-gp inducer, has shown an effect in reducing 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 but does not affect the bioavailability of the active antipsychotic fraction. It is unlikely that this interaction will cause a clinically significant effect.

Antifungal agents

• Itraconazole, a potent CYP3A4 inhibitor and P-gp inhibitor, at a dose of 200 mg daily, increases plasma concentrations of the active antipsychotic fraction by approximately 70% when co-administered with risperidone at doses of 2 to 8 mg daily.
• Ketoconazole, a potent CYP3A4 inhibitor and P-gp inhibitor, at a dose of 200 mg daily, increases plasma concentrations of risperidone and decreases plasma concentrations of 9-hydroxyrisperidone.

Antipsychotic agents

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

Antiviral agents

• Protease inhibitors: study data are lacking; since ritonavir is a potent CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and protease inhibitors boosted with ritonavir 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 CYP3A4 inhibitor and P-gp inhibitor, 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 CYP2D6 inhibitor, increases plasma concentrations of risperidone but less so than the concentration of the active antipsychotic fraction.
• Paroxetine, a potent CYP2D6 inhibitor, increases plasma concentrations of risperidone but (at doses up to 20 mg daily) less so 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 CYP2D6 inhibitor, and fluvoxamine, a weak CYP3A4 inhibitor, at doses up to 100 mg daily, do not cause clinically significant changes in the concentration of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg daily may increase the concentration of the active antipsychotic fraction of risperidone.

Effect of risperidone on the pharmacokinetics of other medicinal products.

Antiepileptic drugs

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

Antipsychotic agents

• 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 precautions" 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 was observed in geriatric patients with dementia who were treated with atypical antipsychotic drugs compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including Risperdal®. In a placebo-controlled study using Risperdal® in this patient population, the incidence of fatal cases 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) antipsychotic drugs had a slightly higher risk of mortality compared to patients not receiving antipsychotics. Based on available study data, the exact level of this risk cannot be determined, and the reason for the increased risk is unknown.

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 only with risperidone (3.1%; mean age: 84 years, range: 70–96 years) or only with furosemide (4.1%; mean age: 80 years, range: 67–90 years). Increased mortality in patients treated with risperidone and furosemide together was observed in two out of four clinical trials. No increased mortality rate was observed in patients who received risperidone concomitantly with other diuretics.

No pathophysiological mechanisms have been established to explain this observation. The cause of death was also not uniform. However, particular caution should be exercised when prescribing the drug in such cases, and a risk-benefit assessment of this combination or combination with other potential diuretics should be performed before prescribing. No increased mortality was observed in patients who received risperidone with other diuretics. Dehydration, regardless of treatment, was a common risk factor for mortality and should be carefully monitored in patients with dementia.

Cerebrovascular adverse reactions.

In placebo-controlled clinical trials in patients with dementia treated with Risperdal®*, a higher incidence (approximately three times higher) of cerebrovascular adverse events (strokes and transient ischemic attacks), including fatal outcomes, was observed compared to those receiving placebo (mean age: 85 years; range: 73–97 years).

Pooled data from six placebo-controlled trials involving elderly patients with dementia (aged 65 years and older) showed cerebrovascular disorders (serious and non-serious, combined) in 3.3% (33/1009) of patients treated with Risperdal® compared to 1.2% (8/712) of patients receiving placebo. The ratio between the Risperdal® and placebo groups (odds ratio; 95% CI) 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 antipsychotic drugs or other patient groups. Risperdal® should be used with caution in patients with risk factors for stroke.

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

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

For persistent aggression in patients with moderate to severe Alzheimer's disease, Risperdal® 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 evaluated, and the need for continued therapy should be reassessed.

Orthostatic hypotension.

Due to the α1-blocking activity of risperidone, orthostatic hypotension may occur, especially at the beginning of treatment. Clinically significant hypotension has been observed during post-marketing experience with concomitant use of risperidone and antihypertensive agents. Risperdal® should be used with caution in patients with cardiovascular disorders (such as heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disorders). In such cases, the dose 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), treatment with risperidone should be discontinued, and leukocyte counts should be monitored until recovery.

Tardive dyskinesia/extrapyramidal symptoms.

Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly 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 appear, discontinuation of all antipsychotic drugs should be considered.

Caution should be exercised when co-administering psychostimulants (e.g., methylphenidate) with risperidone, as extrapyramidal symptoms may occur when adjusting the dose of either or both agents. Gradual withdrawal of psychostimulant treatment is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neuroleptic malignant syndrome.

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

Parkinson's disease and dementia with Lewy bodies.

Physicians should carefully consider the risks of using antipsychotic agents, including Risperdal®, in patients with Parkinson's disease or dementia with Lewy bodies (see section "Contraindications"). 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 increased sensitivity to antipsychotic drugs (e.g., confusion, reduced pain sensitivity, postural instability with frequent falls, in addition to extrapyramidal symptoms).

Hyperglycemia and diabetes mellitus.

Cases of hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with Risperdal®.

In some cases, pre-existing obesity, which could be a triggering factor, was reported. Very rarely, ketoacidosis and rarely diabetic coma have been reported. Appropriate clinical monitoring according to standard antipsychotic use guidelines is recommended. Patients receiving any atypical antipsychotic agents, including Risperdal®, 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 Risperdal® use. Weight monitoring is recommended.

Hyperprolactinemia.

Hyperprolactinemia is a common adverse effect during Risperdal® treatment. Monitoring of prolactin levels is recommended in patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, and galactorrhea).

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

QT interval prolongation.

QT interval prolongation has been reported very rarely in the post-marketing period. As with other antipsychotic drugs, risperidone should be used with caution in patients with known cardiovascular disorders, family history of QT prolongation, bradycardia, or electrolyte imbalances (hypokalemia, hypomagnesemia), as these may increase the risk of arrhythmogenic effects. Caution is also required when risperidone is used concomitantly with other medicinal products that prolong the QT interval.

Seizures.

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

Priapism.

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

Body temperature regulation.

Antipsychotic medicinal products may impair the body's ability to reduce core body temperature. Appropriate care is recommended for patients treated with Risperdal® who may be exposed to conditions that can cause elevated core body temperature, such as intense physical exercise, exposure to high environmental temperatures, concomitant therapy with anticholinergic drugs, or dehydration.

Anti-emetic effect.

In preclinical studies, risperidone demonstrated anti-emetic properties. This property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, or brain tumors.

Hepatic and renal function impairment.

Patients with impaired renal function have a reduced ability to eliminate the active antipsychotic fraction of the drug compared to adults with normal renal function. In patients with impaired hepatic 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 medicinal products. Since patients treated with antipsychotics often have acquired risk factors for venous thromboembolism, all possible risk factors for thromboembolism should be identified before and during Risperdal® 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 Risperdal®.

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 medicinal products. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risk of discontinuing antipsychotic treatment should be carefully weighed.

Children.

Before prescribing Risperdal® to children or adolescents with behavioral disorders, a careful risk-benefit assessment should be performed, and physical and social causes of aggressive behavior, such as pain stimuli or inappropriate response to the environment, should be evaluated.

The sedative effect of risperidone should be carefully monitored in pediatric patients due to potential effects on learning ability. Adjusting the time of risperidone administration may improve the impact of sedation on attention and concentration in children and adolescents.

Risperidone use is associated with minor increases in body weight and body mass index (BMI). Baseline weight measurement is recommended before starting treatment, and regular weight monitoring during treatment is advised. Growth changes 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 height, body weight, 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 antipsychotic drugs. 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 influences bone growth, or whether better disease control leads to greater growth.

During risperidone treatment, extrapyramidal symptoms and other movement disorders should be regularly monitored.

For dosage recommendations in children, see section "Dosage and administration".

Excipients.

Film-coated tablets contain lactose. Patients with hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome should not take Risperdal® film-coated tablets.

Contains the colorant sunset yellow FCF (E 110), which may cause allergic reactions.

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 signs of reproductive toxicity were noted. The potential risk to humans is unknown.

Newborns whose mothers used antipsychotic agents (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, drowsiness, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be carefully monitored.

Risperdal® is not recommended during pregnancy except in cases of essential medical need. If discontinuation of Risperdal® treatment during pregnancy is necessary, it should not be done abruptly.

Breastfeeding.

In animal studies, risperidone and 9-hydroxyrisperidone were excreted in breast milk. Observations suggest that risperidone and 9-hydroxyrisperidone may also be excreted in human breast milk. There are no data on adverse reactions in breastfed infants. Therefore, the benefits of breastfeeding and potential risks to the infant should be weighed.

Fertility

Like other medicinal products that are dopamine D2-receptor antagonists, Risperdal® 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 such effects were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

Risperdal® may have a minor or moderate effect on the ability to drive due to its potential effects on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving and operating machinery until their individual sensitivity to the drug is known.

Dosage and Administration

To achieve a dosage of 0.25–1.5 mg, Risperdal® oral solution should be used. To achieve a dosage of 1 mg, the tablet should be divided in half.

Dosage

Schizophrenia

Adults

Risperdal® can be administered once or twice daily.

Treatment should be initiated at 2 mg of Risperdal® per day. On the second day, the dose may be increased to 4 mg. After this, the dose may be maintained unchanged or, if necessary, further individual dose adjustments may be made.

The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or lower initial and maintenance doses.

Doses exceeding 10 mg of risperidone per day have not demonstrated greater efficacy compared to lower doses, but may increase the risk of extrapyramidal symptoms.

The safety of doses exceeding 16 mg per day has not been studied.

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, increasing by 0.5 mg twice daily.

Children

The use of this medicinal product is not recommended in children (under 18 years of age).

Manic episodes in bipolar disorder

Adults

The recommended initial dose of Risperdal® is 2 mg once daily. The dose may be individually increased by increments of 1 mg/day no more frequently than every 24 hours. The recommended dose range is 1–6 mg per day. 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, long-term use of Risperdal® should be periodically reviewed and adjusted throughout 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, increasing by 0.5 mg twice daily. Since experience with use in elderly patients is limited, caution is recommended.

Children

The use of this medicinal product is not recommended in children (under 18 years of age).

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

The recommended initial dose is 0.25 mg twice daily. Risperdal® 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 may be 1 mg twice daily.

Risperdal® 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 Risperdal® should be periodically reviewed and adjusted throughout 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 increments of 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 dose of no more than 0.5 mg once daily may be sufficient to achieve a positive effect, 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. Risperdal® oral solution is the recommended dosage form for a 0.25 mg dose. If necessary, the dose may be adjusted by increments of 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, a dose of 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 Risperdal® should be periodically reviewed and adjusted throughout therapy.

Children

The use of this medicinal product is not recommended in children under 5 years of age.

Patients with hepatic or renal impairment

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

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

Risperdal® should be used with caution in this patient population.

Administration

Risperdal® is intended for oral administration. Food intake does not affect the absorption of Risperdal®.

At the end of treatment, gradual discontinuation of the medicinal product is recommended. After abrupt discontinuation of high doses of antipsychotic agents, isolated cases of acute withdrawal symptoms have been observed, including nausea, vomiting, sweating, and insomnia (see section "Adverse Reactions"). Psychotic symptoms may also recur, and cases of involuntary movements (such as akathisia, dystonia, and dyskinesia) have been reported.

Switching from therapy with other antipsychotic agents

If clinically appropriate, it is recommended to gradually discontinue previous antipsychotic therapy when initiating treatment with Risperdal®. If a patient is being switched from depot antipsychotic therapy, treatment with Risperdal® should be initiated instead of the next scheduled injection. The need for continuing current antiparkinsonian therapy should be periodically evaluated.

Children

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

Overdose

Symptoms
Signs and symptoms observed in overdose are the known adverse reactions to the drug, manifested in an intensified form: somnolence and sedation, tachycardia and hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported in cases of overdose. Atrial fibrillation/flutter has been reported in association with overdose of Risperdal® in combination with paroxetine.

In cases of acute overdose, the possibility of ingestion of multiple medicinal products should be considered.

Treatment
Ensure and maintain a patent airway to provide adequate ventilation and oxygenation. Administration of activated charcoal together with a laxative should be considered within one hour of drug ingestion. Cardiovascular monitoring, including continuous ECG recording to detect possible arrhythmias, is indicated. Risperidone has no specific antidote; therefore, appropriate supportive measures should be implemented. In cases of acute overdose, potential drug interactions involving multiple agents should be evaluated. Hypotension and vascular collapse should be treated with measures such as intravenous fluids and/or sympathomimetic agents. In the event of acute extrapyramidal symptoms, anticholinergic agents should be administered. Continuous medical monitoring 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 (≥1/10000 to <1/1000), very rare (<1/10000), and not known (frequency cannot be estimated from available data).

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

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

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

c Not observed in clinical studies of Ryspoliptu®, but identified during post-marketing surveillance.

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

Dystonia includes dystonia, hypertonia, torticollis, involuntary muscle contractions, myogenic contractures, blepharospasm, eye movement disorders, tongue paralysis, tic (in the facial area), laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, trismus. A broader list of symptoms is included, not necessarily of extrapyramidal origin. Insomnia includes difficulty falling asleep, intrasomnic disturbances. Seizures include major epileptic seizure. Menstrual disorders include irregular menstruation, oligomenorrhea. Edema includes generalized edema, peripheral edema, pitting edema.

Adverse reactions of paliperidone

Paliperidone is an 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 use, which may also potentially occur with Ryspoliptu®.

Adverse reactions associated with antipsychotic medicinal products

QT interval prolongation

As with other antipsychotics, QT interval prolongation has been reported during the post-marketing period with risperidone use. Other cardiac adverse reactions associated with QT interval prolongation have also been reported with antipsychotic drugs, such as ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and flutter-fibrillation.

Venous thromboembolism

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

Weight gain

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

In pediatric populations with behavioral disorders, during long-term studies, patients' body weight increased on average by 7.3 kg after 12 months of treatment. The expected annual weight gain for children with normal body weight aged 5–12 years is 3 to 5 kg. Starting at age 12, annual weight gain remains at 3 to 5 kg for girls, while boys gain on average 5 kg per year.

Additional information regarding 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 adverse reactions reported during clinical trials with frequencies of 1.4% and 1.5%, respectively, in elderly patients with dementia. Additionally, the following adverse reactions were 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 to 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 has not been fully studied (see section "Special precautions for use").

Excipients content

Contains sunset yellow FCF (E 110), which may cause allergic reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging.

10 film-coated tablets per blister made of PVC/PE/PVDC/aluminum foil, with 2 or 6 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Janssen-Cilag S.p.A. / Janssen Cilag S.p.A.

Manufacturer's location and address of place of business.

Via S. Janssen, 04100 Borgo S. Michele, Latina, Italy /
Via S. Janssen, 04100 Borgo S. Michele, Latina, Italy.