Risperon
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RISPERON® (RISPERON)
Composition:
Active substance: risperidone;
1 film-coated tablet contains risperidone 2 mg or 4 mg;
Excipients: anhydrous lactose, microcrystalline cellulose, pregelatinized starch, magnesium stearate, hypromellose 6, macrogol 6000, titanium dioxide (E 171).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
2 mg film-coated tablets: white, oval, biconvex tablets with a score line and the imprint "T2";
4 mg film-coated tablets: white, oval, biconvex tablets with a score line and the imprint "T4".
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 relates to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor inhibition and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.
Pharmacokinetics
Risperon® in the form of orally disintegrating tablets and oral solution are bioequivalent to 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, peak concentrations are reached 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 administration in solution form. Food does not affect drug absorption; therefore, risperidone can be administered independently of meals. Absolute bioavailability is 66% in fast metabolizers and 82% in slow metabolizers.
Distribution
Risperidone rapidly distributes throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and α1-acid glycoprotein. Risperidone is 90% protein-bound in plasma, while 9-hydroxyrisperidone is 77% protein-bound. Steady-state concentrations of risperidone in the body are achieved within 1 day in most patients. Steady-state concentrations of 9-hydroxyrisperidone are achieved within 4–5 days.
Biological Transformation 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. The cytochrome CYP2D6 is subject to genetic polymorphism. In fast metabolizers, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, conversion occurs much more slowly. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in fast metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both fast and slow metabolizers of cytochrome CYP2D6.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Approximately one week after 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 of risperidone is approximately 3 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, up to 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 these patients have a 43% higher concentration 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 approximately 48% of that in adults with normal renal function. In adult patients with severe renal impairment, clearance was approximately 31% of that in adults with normal renal function. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (about 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (about 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.
Clinical characteristics.
Indications.
Treatment of schizophrenia;
− treatment of manic episodes of moderate to severe intensity in bipolar disorders;
− short-term treatment (up to 6 weeks) of marked aggression in patients with moderate to severe Alzheimer's type dementia when there is a threat of harm to self or others and lack of response to non-pharmacological treatment approaches (see sections "Special precautions" and "Dosage and administration");
− symptomatic short-term treatment (up to 6 weeks) of marked aggression associated with behavioral disorders in children aged 5 years and adolescents with intellectual development below average or intellectual disability diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other destructive behavior requires pharmacological intervention. Pharmacological treatment should be an integral part of a comprehensive treatment program including psychological support and educational interventions. It is recommended that risperidone be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or by a physician experienced in managing behavioral disorders in children and adolescents.
Contraindications.
Hypersensitivity to the active ingredient or to any of the excipients of the medicinal product.
Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances).
Dementia and suspected dementia with Lewy bodies (at least two of the following symptoms in addition to dementia: 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 concomitantly 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.
Risperidone may exhibit antagonistic effects toward 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 used.
Medicinal products with hypotensive effect.
Clinically significant hypotension has been reported during post-marketing experience with concomitant use of risperidone and antihypertensive medicinal products.
Psychostimulants.
Concomitant use of risperidone 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 administration of oral risperidone with paliperidone is not recommended, since paliperidone is the 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 risperidone.
Risperidone is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that 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 risperidone with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but to a lesser extent than 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, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should reconsider the dose of risperidone.
Inhibitors of CYP3A4 and P-gp.
Concomitant use of risperidone 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 inhibitors of CYP3A4 and/or P-glycoprotein, the physician should reconsider the dose of risperidone.
Inducers of CYP3A4 and P-gp.
Concomitant use of risperidone 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 reconsider the dose of risperidone. The effect of CYP3A4 inducers depends on duration, with maximum impact potentially reached at least 2 weeks after initiation of treatment. Accordingly, after cessation of the inducer, induction of CYP3A4 may persist for at least 2 weeks.
Medicinal products with high protein binding.
When risperidone is used concomitantly with other medicinal products that are highly bound to plasma proteins, clinically significant displacement of either drug from protein binding has not been observed. When used concomitantly with such a medicinal product, the prescribing information of that product regarding metabolic pathways and need for dose adjustment should be consulted.
Children.
Interaction studies have been conducted only in adult patients. It is unknown whether the results obtained can be extrapolated to children.
Concomitant use of psychostimulants (e.g., methylphenidate) with risperidone in children did not affect the pharmacokinetics or efficacy of risperidone.
Effect of other medicinal products on the pharmacokinetics of risperidone.
Antibacterial medicinal products
- Erythromycin, a moderate inhibitor of CYP3A4 and 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 of risperidone.
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 been shown to reduce plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may occur 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 would 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 administered 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: data are lacking; since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, 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 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 have minimal effect on 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 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 active antipsychotic fraction. However, higher doses of paroxetine may increase concentrations 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 concentrations of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg daily may increase concentrations of the active antipsychotic fraction of risperidone.
Effect of risperidone on the pharmacokinetics of other medicinal products.
Antiepileptic medicinal products
- Risperidone has no clinically significant effect on the pharmacokinetics of valproate or topiramate.
Antipsychotic medicinal products
- Aripiprazole, a substrate of CYP2D6 and CYP3A4: oral or injectable formulations of risperidone do not affect the pharmacokinetics of aripiprazole or its active metabolite dehydroaripiprazole.
Cardiac glycosides
- Risperidone has no clinically significant effect on the pharmacokinetics of digoxin.
Lithium
- Risperidone has no clinically significant effect on the pharmacokinetics of lithium.
Concomitant use of risperidone with furosemide.
See section "Special 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 rate of mortality was observed in elderly patients with dementia treated with atypical antipsychotic drugs compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotics, including risperidone. In a placebo-controlled trial using risperidone in this patient population, the incidence of fatal events was 4.0% compared to 3.1% in the placebo group. The odds ratio (95% confidence interval) was 1.21 (0.7; 2.1). The mean age of patients who died was 86 years (range: 67–100 years).
Data from two large observational studies indicate that elderly patients with dementia treated with conventional (typical) antipsychotics have a slightly higher risk of mortality compared to patients not receiving antipsychotics. Based on available 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 trial in elderly patients with dementia, an increased mortality rate was observed when risperidone was used concomitantly with furosemide (7.3%; mean age: 89 years, range: 75–97 years), compared to patients treated with risperidone alone (3.1%; mean age: 84 years, range: 70–96 years) or furosemide alone (4.1%; mean age: 80 years, range: 67–90 years). Increased mortality in patients treated with risperidone and furosemide together was observed in 2 out of 4 clinical trials. No increased mortality was observed in patients who received risperidone concomitantly with other diuretics.
The pathophysiological mechanisms explaining this observation have not been established. The cause of death was not uniform. However, particular caution should be exercised when prescribing this combination, and a careful assessment of risks and benefits of this combination or combinations with other potential diuretics should be conducted before prescribing. 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 Risperon**®**, a higher incidence (approximately 3 times) of cerebrovascular adverse events (strokes and transient ischemic attacks), some fatal, 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) occurred in 3.3% (33/1009) of patients treated with risperidone compared to 1.2% (8/712) of patients receiving placebo. The odds ratio (95% CI) between risperidone and placebo groups was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk of cerebrovascular adverse events cannot be ruled out for other antipsychotics or other patient populations. Risperidone should be used with caution in patients with risk factors for stroke.
The risk of cerebrovascular adverse events 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 risperidone to elderly patients with dementia, particularly the risk of stroke, should be carefully weighed. 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 risperidone therapy, should be promptly considered.
For persistent aggression in patients with moderate to severe Alzheimer's disease, risperidone should be prescribed only for short-term use as an adjunct to non-pharmacological interventions that have shown limited or no efficacy, and only when there is no potential risk of harm to self or others.
During treatment, patients should be regularly assessed, and the need for continued therapy should be re-evaluated.
Orthostatic hypotension
Due to the α1-blocking activity of risperidone, particularly at the beginning of treatment, orthostatic hypotension may occur. Clinically significant hypotension has been reported during post-marketing use when risperidone was used concomitantly with antihypertensive agents. Risperidone should be used with caution in patients with cardiovascular disorders (such as heart failure, myocardial infarction, conduction disorders, dehydration, hypovolemia, or cerebrovascular disease). 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 antipsychotics, 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 in the absence of other causes.
Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. In cases of severe neutropenia (<1×10⁹/L), risperidone treatment should be discontinued, and leukocyte counts should be monitored until recovery.
Tardive dyskinesia / extrapyramidal symptoms
Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly of the tongue and/or face), has been observed during treatment with dopamine receptor antagonist drugs. 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 agents. Gradual withdrawal of psychostimulants 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 risperidone, should be discontinued.
Parkinson's disease and dementia with Lewy bodies
Physicians should carefully consider the risks of using antipsychotics, including risperidone, 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 antipsychotics (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 risperidone treatment.
In some cases, pre-existing obesity, which may 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 antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should be regularly assessed for worsening glucose control.
Weight gain
Cases of significant weight gain have been reported during risperidone treatment. Weight monitoring is recommended.
Hyperprolactinemia
Hyperprolactinemia is a common adverse effect of risperidone 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 the growth of human breast tumor cells. Although a clear clinical or epidemiological link with antipsychotic use has not been established, risperidone should be prescribed with caution in patients with relevant medical history. Risperidone should be used cautiously in patients with hyperprolactinemia or prolactin-dependent tumors.
QT interval prolongation
QT interval prolongation has been reported very rarely in the post-marketing period. As with other antipsychotics, 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
Risperidone should be used with caution in patients with a history of seizures or other conditions that may lower the seizure threshold.
Priapism
Priapism may occur during risperidone 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 monitoring is recommended for patients receiving risperidone 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 property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, or brain tumors.
Hepatic and renal 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").
Venous 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 risperidone treatment, and appropriate preventive measures should be taken.
Intraoperative floppy iris syndrome (IFIS)
Intraoperative floppy iris syndrome has been observed during cataract surgery in patients treated with α1-adrenergic receptor antagonists, including risperidone.
IFIS may increase the risk of ocular surgical complications during and after surgery. The ophthalmic surgeon should be informed of past or current use of antipsychotic medicinal products. The potential benefits of discontinuing α1-blocking agents before surgery are not established, and the risk of discontinuing antipsychotic therapy should be carefully considered.
Children
Before prescribing risperidone to children or adolescents with behavioral disorders, the risk-benefit ratio should be carefully evaluated, and physical and social causes of aggressive behavior, such as 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 time of risperidone administration may improve the impact of sedation on children's and adolescents' ability to concentrate.
Risperidone use is associated with minor increases in body weight and body mass index (BMI). Initial body weight measurement before treatment initiation and regular monitoring during treatment are recommended. Growth changes observed in long-term open-label extension studies were within expected age-related norms. The impact of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.
Due to the potential impact of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including measurement of height, 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 antipsychotics. However, the data from this study are insufficient to determine whether risperidone affects final adult height, whether the measurements are directly related to risperidone's effect on bone growth, whether the underlying disease affects bone growth, or whether this is a result of better disease control leading to greater height gain.
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, lactase deficiency, or glucose-galactose malabsorption should not take Risperon® film-coated tablets.
Use during pregnancy or breastfeeding.
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 in humans is unknown.
Newborns whose mothers used antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of developing reversible extrapyramidal symptoms and/or withdrawal syndrome. These symptoms include agitation, abnormally increased or decreased muscle tone, tremor, somnolence, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be carefully monitored.
Risperon® is not recommended during pregnancy except in cases of life necessity. If discontinuation of Risperon® 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 carefully weighed.
Fertility.
Like other medicinal products that are dopamine D2 receptor antagonists, Risperon® 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.
The medicinal product may have a slight or moderate effect on the ability to drive due to its potential impact on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving or operating machinery until their individual sensitivity to the medicinal product is known.
Administration and Dosage
To achieve dosing of 0.25–1.5 mg, risperidone oral solution is used. To achieve a dose of 1 mg, a 2 mg tablet is divided in half.
Dosage
Schizophrenia
Adults
Risperon® may be administered once or twice daily.
Treatment should be initiated at 2 mg of Risperon® per day; on the second day, the dose may be increased to 4 mg. After that, 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 reduced initial and maintenance doses.
Doses exceeding 10 mg of risperidone per day have not demonstrated higher efficacy compared to lower doses, but may increase the risk of extrapyramidal symptoms.
The safety of doses above 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 Risperon® is 2 mg once daily. The dose may be individually increased by 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 Risperon® 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 clinical experience in elderly patients is limited, caution is recommended.
Children
The use of the drug is not recommended in children (under 18 years of age).
Short-term treatment of marked aggression in patients with Alzheimer's type dementia
The recommended initial dose is 0.25 mg twice daily. Risperidone oral solution is the recommended dosage form for a 0.25 mg dose. If necessary, the dose may be increased by increments of 0.25 mg twice daily, no more frequently than every other day. For most patients, the optimal dose is 0.5 mg twice daily. However, for some patients, an effective dose may be 1 mg twice daily.
Risperon® should not be used for longer than 6 weeks in patients with marked aggression due to Alzheimer's disease. As with other forms of symptomatic treatment, the use of Risperon® should be periodically reviewed and adjusted throughout therapy.
Short-term symptomatic treatment (up to 6 weeks) of marked 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 increasing by 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. Risperidone oral solution is the recommended dosage form for a 0.25 mg dose. If necessary, the dose may be adjusted by increasing by 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 Risperon® should be periodically reviewed and adjusted throughout 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, the plasma concentration of the free fraction of risperidone is increased.
Regardless of the indication, these patients should receive half of the initial and maintenance doses, and dose titration should be slower.
Risperon® should be used with caution in this patient group.
Administration
Risperon® is intended for oral administration. Food intake does not affect the absorption of Risperon®.
At the end of treatment, gradual discontinuation of the drug 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, previous antipsychotic therapy should be gradually discontinued when initiating treatment with Risperon®. When switching from depot antipsychotic formulations, treatment with Risperon® should be initiated instead of the next scheduled injection. The need for continuing concomitant antiparkinsonian medication should be periodically evaluated.
Children
Risperidone is used for the treatment of marked aggression in behavioral disorders in children aged 5 years and older.
Overdose
Symptoms
Signs and symptoms observed in overdose are the known adverse reactions of the drug, but in an exaggerated 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 associated with overdose of Risperon® in combination with paroxetine has also been reported.
In cases of acute overdose, the possibility of ingestion of multiple drugs should be considered.
Treatment
Ensure and maintain a patent airway to provide adequate ventilation and oxygenation. Administration of activated charcoal combined 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. Arterial hypotension and vascular collapse should be treated with measures such as intravenous fluids and/or sympathomimetic agents. In case of acute extrapyramidal symptoms, anticholinergic agents should be administered. Continuous medical monitoring should be maintained until complete recovery of the patient.
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.
| Infections and infestations |
|
| Common |
pneumonia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, ear infections, influenza |
| Uncommon |
respiratory tract infections, cystitis, eye infections, tonsillitis, onychomycosis, cellulitis, localized infection, viral infection, acrodermatitis |
| Rare |
infection |
| Blood and lymphatic system disorders |
|
| Uncommon |
neutropenia, decreased white blood cell count, thrombocytopenia, anemia, decreased hematocrit, increased eosinophils |
| Rare |
agranulocytosis |
| Immune system disorders |
|
| Uncommon |
hypersensitivity |
| Rare |
anaphylactic reaction |
| Endocrine system disorders |
|
| Common |
hyperprolactinemia |
| Rare |
disorders of antidiuretic hormone secretion, presence of glucose in urine |
| Metabolism and nutrition disorders |
|
| Common |
weight gain, increased appetite, decreased appetite |
| Uncommon |
diabetes mellitus, hyperglycemia, polydipsia, weight loss, anorexia, increased cholesterol level |
| Rare |
water intoxication, hypoglycemia, hyperinsulinism, increased blood triglycerides |
| Very rare |
diabetic ketoacidosis |
| Psychiatric disorders |
|
| Very common |
insomnia |
| Common |
sleep disorders, agitation, depression, anxiety |
| Uncommon |
mania, confusion, decreased libido, restlessness, night terrors |
| Rare |
catatonia, somnambulism, sleep-related eating disorder, blunted affect, anorgasmia |
| Nervous system disorders |
|
| Very common |
sedation/somnolence, parkinsonism, headache |
| Common |
akathisia, dystonia, dizziness, dyskinesia, tremor |
| Uncommon |
late dyskinesia, cerebral ischemia, unresponsiveness to stimuli, loss of consciousness, depressed level of consciousness, seizures, syncope, psychomotor hyperactivity, balance disorders, coordination impairment, postural dizziness, attention disturbances, dysarthria, taste disturbances, hypoesthesia, paresthesia |
| Rare |
malignant neuroleptic syndrome, cerebrovascular disorders, diabetic coma, rhythmic head bobbing |
| Eye disorders |
|
| Common |
blurred vision, conjunctivitis |
| Uncommon |
photophobia, dry eyes, increased lacrimation, eye redness |
| Rare |
glaucoma, eye movement disorders, rotatory nystagmus, eyelid crusting, intraoperative floppy iris syndrome |
| Ear and labyrinth disorders |
|
| Uncommon |
vertigo, tinnitus, ear pain |
| Cardiac disorders |
|
| Common |
tachycardia |
| Uncommon |
atrial fibrillation, atrioventricular block, cardiac conduction disorders, QT interval prolongation on electrocardiogram, bradycardia, electrocardiogram abnormalities, palpitations |
| Rare |
sinus arrhythmia |
| Vascular disorders |
|
| Common |
arterial hypertension |
| Uncommon |
hypotension, orthostatic hypotension, flushing |
| Rare |
pulmonary embolism, venous thrombosis |
| Respiratory system disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening of airway patency, wheezing, stridor, dysphonia, respiratory disorders |
| Rare |
sleep apnea syndrome, hyperventilation |
| Gastrointestinal disorders |
|
| Common |
abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache |
| Uncommon |
fecal incontinence, fecal impaction, gastroenteritis, dysphagia, abdominal distension |
| Rare |
pancreatitis, gastrointestinal obstruction, tongue swelling, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
elevated transaminases, elevated gamma-glutamyl transferase, elevated liver enzymes |
| Rare |
jaundice |
| Skin and subcutaneous tissue disorders |
|
| Common |
rash, erythema |
| Uncommon |
urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discoloration, acne, seborrheic dermatitis, skin disorders, skin injury |
| Rare |
drug rash, dandruff |
| Very rare |
angioedema |
| Not known |
Stevens-Johnson syndrome/toxic epidermal necrolysis |
| Musculoskeletal system disorders |
|
| Common |
muscle spasms, musculoskeletal pain, back pain, arthralgia |
| Uncommon |
increased creatine phosphokinase, abnormal posture, joint stiffness, joint swelling, muscle weakness, neck pain |
| Rare |
rhabdomyolysis |
| Renal and urinary disorders |
|
| Common |
urinary incontinence |
| Uncommon |
polyuria, urinary retention, dysuria |
| Pregnancy, puerperium and perinatal conditions |
|
| Very rare |
drug withdrawal syndrome in newborns |
| Reproductive system and breast disorders |
|
| Uncommon |
erectile dysfunction, ejaculation disorder, amenorrhea, menstrual cycle irregularity, gynecomastia, galactorrhea, sexual dysfunction, breast pain, vaginal discharge |
| Rare |
priapism, menstrual delay, breast engorgement, breast enlargement, nipple discharge |
| General disorders |
|
| Common |
edema, fever, chest pain, asthenia, fatigue, pain |
| Uncommon |
facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, fever, unusual sensations, discomfort |
| Rare |
hypothermia, decreased body temperature, cold sensation in extremities, drug withdrawal syndrome, induration |
| Injury and poisoning |
|
| Common |
falls |
| Uncommon |
postoperative pain |
a Hyperprolactinemia in some cases may lead to gynecomastia, menstrual disorders, amenorrhea, galactorrhea.
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 risperidone, 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), 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, which may not necessarily have an extrapyramidal origin. Insomnia includes: difficulty falling asleep, intrasomniac disorder. Seizures include: grand mal seizure. Menstrual disorders include: irregular menstruation, oligomenorrhea. Edema includes: generalized edema, peripheral edema, pitting edema.
Adverse reactions of paliperidone
Paliperidone is the active metabolite of risperidone; therefore, the adverse reaction profiles of these substances (including oral and injectable formulations) are similar. In addition to the adverse reactions listed above, postural orthostatic tachycardia syndrome has been reported with paliperidone use, which may also likely occur during Risperon® use.
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 antipsychotic use that may prolong the QT interval include 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 therapy.
Weight gain
Comparison of the number of patients treated with Risperon® versus placebo-treated patients who experienced ≥7% body weight gain in placebo-controlled trials lasting 6 to 8 weeks showed a statistically significant difference in the frequency of weight gain in the Risperon® group (18%) compared to the placebo group (9%). In three-week placebo-controlled trials in adult patients with acute mania, the frequency of weight gain ≥7% was similar in the Risperon® 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, weight gain for girls remains at 3 to 5 kg per year, while boys gain on average 5 kg per year.
Additional information regarding specific patient populations
Adverse reactions reported more frequently in elderly patients with dementia or in children than in adults are described below.
Elderly patients with dementia
Transient ischemic attack and cerebrovascular disorders were adverse reactions reported in 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 sufficiently studied.
Shelf life. 3 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging.
10 tablets per blister; 1 blister or 3 or 6 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
BALKANFARMA-DUPNITSA AD / BALKANPHARMA-DUPNITSA AD.
Manufacturer's address and location of operations.
3 Samokovsko Shosse Str., Dupnitsa 2600, Bulgaria.
Marketing authorization holder.
UAB “Farmlyga” / UAB “Farmlyga”.
Address of the marketing authorization holder.
Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.