Risoplept

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

Composition:

Active substance: risperidone;

1 ml of solution contains 1 mg of risperidone;

Excipients: tartaric acid, benzoic acid (E 210), sodium hydroxide, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical characteristics: clear, colorless solution.

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 does not exhibit affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser degree 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® orally disintegrating tablets and Rispolipt® film-coated tablets are bioequivalent to Rispolipt®, oral solution.

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, peak concentrations are reached within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). Food does not affect the absorption of the drug; therefore, risperidone can be administered regardless of food intake. 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 acidic α1-glycoprotein. Risperidone is 90% protein-bound in plasma, while 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.

Metabolism and Elimination

Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which has a pharmacological effect similar to risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. CYP2D6 is subject to genetic polymorphism. In rapid metabolizers, risperidone is rapidly 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 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. Within 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, 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

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 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, plasma concentrations of risperidone were within normal range, 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 did not reveal any significant influence of sex, age, 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 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, in whom the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological treatment should be an integral part of a comprehensive treatment program that includes psychological support and educational measures. It is recommended that Risperdal® be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or 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, gait 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 cautiously 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 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 were observed 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 precautions").

Paliperidone.

Concomitant use of oral Risperdal® with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone and their combination may lead to 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 modulate 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 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 initiation of concomitant therapy, as well as 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 significantly increase plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation of concomitant therapy, as well as upon discontinuation of itraconazole or other potent inhibitors of CYP3A4 and/or P-glycoprotein, 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, as well as 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 is time-dependent, with maximum impact potentially reached at least 2 weeks after initiation of treatment. Accordingly, after discontinuation, 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 medicinal products

• Erythromycin, a moderate inhibitor of CYP3A4 and inhibitor of P-gp, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
• Rifampicin, a potent inducer of CYP3A4 and inducer of P-gp, 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 inducer of P-gp, has demonstrated 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 and does not affect the bioavailability of the active antipsychotic fraction. This interaction is unlikely to cause a clinically significant effect.

Antifungal medicinal products

• Itraconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg daily, increases plasma concentrations of the active antipsychotic fraction by approximately 70% when used concomitantly with risperidone at doses of 2 to 8 mg daily.
• Ketoconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg daily, 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 inhibitor of P-gp, 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 daily) 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 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 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 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 treated with atypical antipsychotic drugs compared to placebo-treated patients in a meta-analysis of 17 controlled trials of atypical antipsychotics, including Risperdal®. In a placebo-controlled trial using Risperdal®, the mortality rate in this patient group 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 geriatric patients with dementia treated with conventional (typical) antipsychotic drugs have a slightly higher risk of death 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 of geriatric 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 among patients treated concomitantly with risperidone and furosemide was observed in two out of four clinical trials. No increased mortality rate was observed in patients who received risperidone concomitantly with other diuretics.

The pathophysiological mechanisms underlying this observation have not been established. The cause of death was not uniform. However, particular caution should be exercised when prescribing this combination, and the risks and benefits of this combination or combinations with other potential diuretics should be carefully evaluated before administration. 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 (CVAE).

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 CVAE cannot be ruled out for other antipsychotic drugs or other patient populations. 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.

The risks and benefits of prescribing Risperdal® 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, speech disturbances, or visual 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 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 reported during the post-marketing period when risperidone was used concomitantly with 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 during the post-marketing period (< 1/10,000 patients).

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 appear 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 occur. 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 observed during treatment with drugs possessing dopamine receptor antagonist properties. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs or symptoms of tardive dyskinesia appear, 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 psychostimulant therapy 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 features include myoglobinuria (rhabdomyolysis) and acute renal failure. If neuroleptic malignant syndrome develops, all antipsychotic drugs, including Risperdal®, must be discontinued.

Parkinson's disease and dementia with Lewy bodies.

Physicians should consider the risks associated with using antipsychotic agents, including Risperdal®, in patients with Parkinson's disease or dementia with Lewy bodies (see section "Contraindications"). The use of risperidone 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, prior obesity was reported, which could be a triggering factor. 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 during treatment with Risperdal®. Monitoring of body weight is recommended.

Hyperprolactinemia.

Hyperprolactinemia is a common adverse effect during treatment with Risperdal®. Patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, and 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 by clinical and epidemiological studies, risperidone should be prescribed with caution to patients with relevant medical history. Risperdal® should be used with caution in patients with hyperprolactinemia and those with prolactin-dependent tumors.

QT interval prolongation.

QT interval prolongation has been reported very rarely during 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 with caution in patients with a history of seizures or other conditions that may potentially lower the seizure threshold.

Priapism.

Priapism may occur during treatment with Risperdal® 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 receiving Risperdal® who are exposed to conditions that may increase core body temperature, such as intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic drugs, or dehydration.

Anti-emetic effect.

In preclinical studies, risperidone demonstrated anti-emetic properties. This effect 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 adult patients 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 potential risk factors for thromboembolism should be identified before and during treatment with Risperdal®, 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 surgical complications during and after surgery. The ophthalmic surgeon should be informed about current or past use of antipsychotic medicinal products. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risk of discontinuing antipsychotic therapy should be carefully considered.

Children.

The risk-benefit ratio should be carefully evaluated before prescribing Risperdal® to children or adolescents with behavioral disorders, and physical and social causes of aggressive behavior (e.g., pain stimuli or inappropriate response to the environment) should be assessed.

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

Risperidone use is associated with mean increases in body weight and body mass index (BMI). Baseline weight measurement is recommended before starting treatment, and regular weight monitoring is advised during treatment. 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 potential effects of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including measurement of height, body 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 antipsychotic drugs. However, the 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 height gain.

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

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

Excipients.

Risperdal® oral solution contains benzoic acid (E 210). Increased bilirubinemia may lead to neonatal jaundice, which may progress to kernicterus (deposition of unconjugated bilirubin in brain tissue).

Use during pregnancy or breastfeeding.

Pregnancy.

No controlled studies have been conducted in pregnant women. Although teratogenic effects were not observed in animal studies, other signs of reproductive toxicity were observed. The potential risk in humans is unknown.

Newborns whose mothers used antipsychotic drugs (including risperidone) during the third trimester of pregnancy are at risk of developing reversible extrapyramidal symptoms and/or withdrawal syndrome. These symptoms include agitation, unusual increase or decrease in muscle tone, tremor, somnolence, 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 life necessity. If discontinuation of Risperdal® therapy during pregnancy is necessary, it should not be stopped 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 carefully 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 secretion of pituitary gonadotropins. 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.

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 are advised to refrain from driving and operating machinery until their individual sensitivity to the drug is known.

Method of Administration and Dosage

Dosage

Schizophrenia

Adults

Rispolipt® can be administered once or twice daily.

Treatment should be initiated at 2 mg of Rispolipt® 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 continued.

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 the drug is not recommended in children (under 18 years of age).

Manic episodes in bipolar disorder

Adults

The recommended initial dose of Rispolipt® 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 to 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 Rispolipt® 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, increasing by 0.5 mg twice daily. Due to limited experience in elderly patients, caution is recommended when administering the drug.

Children

The use of the drug 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. 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.

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

Children

The use of the drug is not recommended in children under 5 years of age.

Patients with hepatic and 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, plasma concentrations of the free fraction of risperidone are increased.

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

Rispolipt® should be used with caution in these patient groups.

Method of Administration

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

At the end of treatment, gradual discontinuation of the medication is recommended. After abrupt discontinuation of high doses of antipsychotics, 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 justified, it is recommended to gradually discontinue previous antipsychotic therapy when initiating treatment with Rispolipt®. When switching from depot antipsychotic formulations, treatment with Rispolipt® should be initiated instead of the next scheduled injection. The need for continuing concomitant antiparkinsonian therapy should be periodically evaluated.

Rispolipt® solution is incompatible with most types of tea, including black tea.

Instructions for self-opening the bottle and using the dropper dispenser

30 ml bottle

To open the bottle and use the dropper, perform the following steps (see Fig. 1–4):

100 ml bottle

To open the bottle and use the pipette, perform the following steps (see Fig. 1–3):

Children.

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

Overdose.

Symptoms.

Observed signs and symptoms of 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. Atrial flutter/fibrillation associated with overdose of Risperdal® in combination with paroxetine has been reported.

In cases of acute overdose, the possibility of concomitant intake 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, if not contraindicated, and only if the patient presents 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 medicinal products should be evaluated. Arterial hypotension and circulatory collapse should be treated with measures such as intravenous fluids and/or sympathomimetic agents. In the event of acute extrapyramidal symptoms, anticholinergic medications 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 (≥ 1/10000 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 Hyperprolactinaemia in some cases may lead to gynaecomastia, menstrual disorders, amenorrhoea, anovulation, galactorrhoea, 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 treated with risperidone.

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

d Extrapyramidal disorders include: parkinsonism (hypersalivation, muscle rigidity, parkinsonism, sialorrhoea, 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, intrasomniac disorder. Seizures include grand mal epileptic seizure. Menstrual disorders include: irregular menstruation, oligomenorrhoea. Oedema includes: generalized oedema, peripheral oedema, pitting oedema.

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 use, which may also potentially occur with Ryspoliptu®.

Adverse reactions common to antipsychotic medicinal products

QT interval prolongation

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

Venous thromboembolism

Cases of venous thromboembolic events, 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 of ≥7% in placebo-controlled trials lasting 6 to 8 weeks demonstrated 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 paediatric populations with behavioural 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 on specific patient categories

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

Elderly patients with dementia

Transient ischaemic 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 oedema, 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, diarrhoea, and enuresis.

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

Shelf life: 3 years. Shelf life after opening the bottle – 3 months.

Storage conditions:

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

Incompatibility: Incompatible with most types of tea, including black tea.

Packaging:

Oral solution in 30 ml and 100 ml bottles, supplied with a dosing pipette, packed in a cardboard box.

Prescription status:

Prescription only.

Manufacturer:

Janssen Pharmaceutica NV / Janssen Pharmaceutica NV

Manufacturer's address and place of business:

Turnhoutseweg 30, Beerse, 2340, Belgium / Turnhoutseweg 30, Beerse, 2340, Belgium.