Neurispin-zdorovia
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE|consumption| of the medicinal product NEIRISPIN-ZDOROVYE (NEIRISPIN-ZDOROVYE)
Composition:
Active substance: risperidone;
1 tablet contains risperidone 1 mg or 2 mg or 4 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, potato starch, povidone, polyethylene glycol 4000, sodium lauryl sulfate, magnesium stearate, colloidal anhydrous silicon dioxide, titanium dioxide (E 171), hypromellose; Candurin (silver shimmer) containing potassium aluminosilicate, titanium dioxide (E 171); colorant: for 2 mg tablets – Yellow West FCF (E 110); for 4 mg tablets – «Sepispers Dry Yellow R» containing methylhydroxypropylcellulose, microcrystalline cellulose, riboflavin (E 101), and «Sepispers Dry Blue I» containing methylhydroxypropylcellulose, microcrystalline cellulose, indigo carmine (E 132).
Medicinal form: Film-coated tablets.
Main physicochemical properties: Film-coated tablets: 1 mg tablets – white in color with a pearly sheen; 2 mg tablets – yellowish-orange in color with a pearly sheen; 4 mg tablets – light green in color with a pearly sheen.
Pharmacotherapeutic group: Antipsychotic agents. ATC code: N05A X08.
Pharmacological properties.
Pharmacodynamics. Risperidone is a selective monoaminergic antagonist with unique properties. It exhibits high affinity for serotonin 5-HT2 and dopamine D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone shows no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which relates to its efficacy against productive symptoms of schizophrenia, it does not cause significant motor activity suppression and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.
Pharmacokinetics. 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%). Relative bioavailability after oral administration of risperidone in tablet form is 94% (CV = 10%) compared to the solution form. Food does not affect drug absorption; therefore, risperidone can be administered 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 binds to albumin and α1-acid 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.
Biotransformation 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. Cytochrome CYP2D6 is subject to genetic polymorphism. In rapid metabolizers, risperidone is quickly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, the conversion is much slower. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in rapid metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both rapid and slow metabolizers of cytochrome CYP2D6.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Within 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 is approximately 3 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, 34 hours.
Linearity. Plasma concentrations of risperidone are proportional to the dose of the drug (within the therapeutic dose range).
Elderly patients and patients with renal or hepatic impairment. A pharmacokinetic study of single-dose administration in elderly patients demonstrated that in these patients, the 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, 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 and 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 habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Clinical characteristics.
Indications.
- Treatment of schizophrenia;
- treatment of manic episodes of moderate to severe degree 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");
- short-term symptomatic treatment (up to 6 weeks) of marked aggression in behavioral disorders in children from 5 years of age 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 the drug 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 drug. 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 types of interactions.
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, certain antimalarials (quinine, mefloquine), and products causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or agents that inhibit hepatic metabolism of risperidone. This list is indicative and incomplete.
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 to levodopa and other dopamine agonists. If such a combination is considered necessary, especially in the terminal stage of Parkinson's disease, the lowest effective doses of each drug should be prescribed.
Medicinal products with hypotensive effect. Clinically significant hypotension has been observed during the post-marketing period with concomitant use of risperidone and antihypertensive medicinal products.
Psychostimulants. The use of risperidone in combination with psychostimulants (e.g., methylphenidate) may lead to the emergence of extrapyramidal symptoms after dose adjustment of one or both agents (see section "Special precautions").
Paliperidone. Concomitant use of oral risperidone with paliperidone is not recommended, as paliperidone is an active metabolite of risperidone and their combination may result in additive effects of the active antipsychotic fraction.
Pharmacokinetic interactions. Food does not affect the absorption of the drug.
Risperidone is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity or are potent inhibitors or inducers of CYP3A4 and/or P-gp activity may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.
Potent CYP2D6 inhibitors. Concomitant use of risperidone with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but to a lesser extent than the concentration of the active antipsychotic fraction. Higher doses of a potent CYP2D6 inhibitor may increase the concentration of the active antipsychotic fraction of risperidone (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are expected to affect plasma concentrations of risperidone similarly. At the start of concomitant therapy, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the risperidone dose.
Inhibitors of CYP3A4 and P-gp. Concomitant use of risperidone with potent inhibitors of CYP3A4 and/or P-gp may significantly 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 review the risperidone dose.
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 beginning of therapy, and upon discontinuation of carbamazepine or other strong inducers of CYP3A4/P-gp, the physician should review the risperidone dose. The effect of CYP3A4 inducers depends on time, with maximum impact potentially achieved at least 2 weeks after initiation of treatment. Accordingly, after discontinuation, induction of CYP3A4 may persist for at least 2 weeks.
Medicinal products with high protein binding. When risperidone is used concomitantly with other medicinal products that are highly bound to plasma proteins, clinically significant displacement of either drug from the protein fraction has not been observed. When used concomitantly with such a medicinal product, the prescribing information of that product should be consulted regarding metabolic pathways and the need for dose adjustment.
Children. Interaction studies have been conducted only in adult patients. It is unknown whether the results obtained can be applied to children.
Concomitant use of psychostimulants (e.g., methylphenidate) with risperidone in children 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 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-gp.
- Topiramate moderately reduces the bioavailability of risperidone and does not affect the bioavailability of the active antipsychotic fraction. It is unlikely that this interaction may cause a clinically significant effect.
Antifungal medicinal products
- Itraconazole, a potent inhibitor of CYP3A4 and 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 plasma 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 from studies 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.
β-blockers
- Some β-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 dehydro-aripiprazole.
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 has been observed in elderly patients with dementia treated with atypical antipsychotic agents compared to placebo-treated patients 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 death was 4% compared to 3.1% in the placebo group. The odds ratio (95% confidence interval) was 1.21 (0.7; 2.1). The mean age of patients who died was 86 years (range: 67–100 years).
Data from two large observational studies indicate that elderly patients with dementia treated with conventional (typical) antipsychotics have a slightly higher risk of death compared to patients not receiving antipsychotics. Based on available data, the exact level of this risk cannot be determined, and the 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 both 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. 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, elderly patients with dementia treated with risperidone showed a higher incidence (approximately three times higher) of cerebrovascular adverse events (strokes and transient ischemic attacks), some fatal, 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) demonstrated cerebrovascular disorders (serious and non-serious, combined) in 3.3% (33/1009) of patients treated with risperidone compared to 1.2% (8/712) of placebo-treated patients. The odds ratio (95% CI) between the risperidone and placebo groups was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk of cerebrovascular adverse events with other antipsychotics or in other patient populations cannot be ruled out. 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.
The risks and benefits of prescribing risperidone to elderly patients with dementia, particularly the risk of stroke, should be carefully weighed. Patients and caregivers should be instructed to report immediately any 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 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 if there is no potential risk of harm to self or others.
Patients should be regularly evaluated during treatment, and the need for continued therapy should be periodically reassessed.
Orthostatic hypotension. Due to the α1-blocking activity of risperidone, orthostatic hypotension may occur, particularly at the beginning of treatment. 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 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 antipsychotics, including risperidone. Agranulocytosis has been reported very rarely (<1/10,000 patients) in the post-marketing period.
Patients with a history of significant leukopenia or drug-induced leukopenia/neutropenia should be closely monitored during the first few months of treatment. Risperidone should be discontinued if signs of a significant decrease in white blood cell count occur and no other causes are identified.
Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. In cases of severe neutropenia (<1×10⁹/L), risperidone treatment should be discontinued, and white blood cell counts should be monitored until recovery.
Tardive dyskinesia/extrapyramidal symptoms. Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly of the tongue and/or face), has been reported with drugs possessing dopamine receptor antagonist properties. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs or symptoms of tardive dyskinesia appear, discontinuation of all antipsychotics 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 tapering 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 neuroleptics, 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 antipsychotics, including risperidone, should be discontinued.
Parkinson's disease and dementia with Lewy bodies. Physicians should consider the risks associated with 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 heightened 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 worsening of pre-existing diabetes have been reported during treatment with risperidone.
In some cases, prior excessive body weight, which could be a triggering factor, was reported. Very rarely, ketoacidosis and rarely, diabetic coma have been reported. Appropriate clinical monitoring according to antipsychotic use guidelines is recommended. Patients receiving any atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, weakness). Diabetic patients should be regularly evaluated for deterioration in glucose control.
Weight gain. Significant weight gain has been reported with risperidone use. Weight monitoring is recommended.
Hyperprolactinemia. Hyperprolactinemia is a common adverse effect of risperidone treatment. Patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, galactorrhea) should have their prolactin levels monitored.
Tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although a clear association with antipsychotic use has not been established in clinical and epidemiological studies, risperidone should be prescribed with caution in patients with a relevant history. The drug should be used cautiously in patients with hyperprolactinemia and prolactin-dependent tumors.
QT interval prolongation. QT interval prolongation has been reported very rarely in the post-marketing period. As with other antipsychotics, risperidone should be used with caution in patients with known cardiovascular disorders, a family history of QT prolongation, bradycardia, or electrolyte imbalances (hypokalemia, hypomagnesemia), as these may increase the risk of arrhythmogenic effects. Caution is also advised when risperidone is used concomitantly with other medicinal products that prolong the QT interval.
Seizures. The drug 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 treatment with the drug due to its α-adrenergic blocking effect.
Body temperature regulation. Antipsychotics may impair the body's ability to reduce core body temperature. Appropriate care is recommended for patients receiving risperidone who may be exposed to conditions that may elevate core body temperature, such as intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic agents, or dehydration.
Antiemetic effect. In preclinical studies, risperidone demonstrated antiemetic 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. In patients with impaired renal function, the ability to eliminate the active antipsychotic fraction of the drug is reduced compared to adult patients with normal renal function. In patients with impaired hepatic function, an increased concentration of free risperidone in plasma is observed (see section "Dosage and administration").
Thromboembolism. Cases of venous thromboembolism have been reported with antipsychotic use. Since patients treated with antipsychotics often have acquired risk factors for venous thromboembolism, all potential risk factors for thromboembolism should be identified before and during 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 intraoperative and postoperative complications during eye surgery. The ophthalmic surgeon should be informed of current or past use of antipsychotics. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risk of discontinuing antipsychotic therapy should be carefully weighed.
Children. The risk-benefit ratio should be carefully considered before prescribing the drug to children or adolescents with behavioral disorders, and physical and social causes of aggressive behavior (e.g., pain stimuli or inappropriate environmental responses) should be evaluated.
The sedative effect of risperidone should be carefully monitored in pediatric patients due to potential effects on learning ability. Adjusting the time of risperidone administration may improve the impact of sedation on attention in children and adolescents.
Risperidone use has been associated with slight increases in body weight and body mass index (BMI). Baseline weight measurement before treatment initiation and regular weight monitoring during treatment are recommended. Growth changes observed in long-term open-label extension studies were within expected age-related norms. The effect of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.
Due to the potential impact of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including measurement of height, body weight, sexual maturation, menstrual cycle, and other prolactin-dependent phenomena, should be considered.
Results from a small post-marketing observational study showed that patients aged 8–16 years receiving risperidone were on average 3.0–4.8 cm taller than those receiving other antipsychotics. However, data from this study are insufficient to determine whether risperidone affects final adult height, whether the measurement results are directly due 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 growth.
Extrapyramidal symptoms and other movement disorders should be regularly monitored during risperidone treatment.
For dosage recommendations in children, see section "Dosage and administration."
Excipients. The medicinal product contains lactose. If the patient has known intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.
Tablets of 2 mg contain the colorant yellow sunset FCF (E 110), which may cause allergic reactions.
Use during pregnancy or breastfeeding.
Pregnancy. Controlled studies in pregnant women have not been conducted. Although teratogenic effects were not observed in animal studies, other manifestations of reproductive toxicity were observed. 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, unusual increase or decrease in muscle tone, tremor, drowsiness, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be carefully monitored.
The drug is not recommended during pregnancy except in cases of essential medical need. If discontinuation of treatment during pregnancy is necessary, it should not be done abruptly.
Breastfeeding. In animal studies, risperidone and 9-hydroxyrisperidone were excreted in breast milk. Observations suggest that risperidone and 9-hydroxyrisperidone may also be excreted in human breast milk. There are no data on adverse reactions in breastfed infants. Therefore, the benefits of breastfeeding and the potential risks to the infant should be carefully weighed.
Fertility. Like other drugs that are dopamine D2 receptor antagonists, risperidone increases prolactin levels.
Hyperprolactinemia may suppress gonadotropin-releasing hormone production in the hypothalamus, leading to decreased 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 drug may have a minor or moderate effect on the ability to drive or operate machinery due to its potential effects on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving or operating machinery until their individual response to the drug is known.
Method of Administration and Dosage.
To obtain the prescribed doses of the medicinal product, risperidone medicinal forms with appropriate active substance content should be used.
Dosing
Schizophrenia
Adults. The drug may be administered once or twice daily.
Treatment should be initiated at 2 mg of risperidone per day; on the second day, the dose may be increased to 4 mg. Thereafter, the dose may be maintained unchanged or, if necessary, further individual dose adjustment may continue.
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 higher efficacy compared to lower doses, but they may cause 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. Use in children (under 18 years of age) is not recommended.
Manic episodes in bipolar disorder
Adults. The recommended initial dose of risperidone 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 the drug should be periodically reviewed and adjusted throughout therapy.
Elderly patients (aged 65 years and older). The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily. Since experience in elderly patients is limited, caution is recommended.
Children. 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 is 1 mg twice daily.
The drug should not be used for longer than 6 weeks in patients with severe aggression due to Alzheimer's disease. As with other forms of symptomatic treatment, the use of the drug should be periodically reviewed and adjusted throughout therapy.
Short-term symptomatic treatment (up to 6 weeks) of severe aggression in behavioral disorders
Children and adolescents aged 5 to 18 years. The recommended initial dose for patients with body weight ≥50 kg is 0.5 mg once daily. If necessary, the dose should be adjusted by adding 0.5 mg once daily no more frequently than every other day. The optimal dose for most patients is 1 mg once daily. However, for some patients, a dose of no more than 0.5 mg once daily is sufficient to achieve a positive effect, whereas others may require 1.5 mg once daily.
The recommended initial dose for patients with body weight <50 kg is 0.25 mg once daily. If necessary, the dose may be adjusted by adding 0.25 mg once daily no more frequently than every other day. The optimal dose for most patients is 0.5 mg once daily. However, for some patients, no more than 0.25 mg once daily is sufficient to achieve a positive effect, whereas others may require 0.75 mg once daily.
As with other forms of symptomatic treatment, the use of the drug should be periodically reviewed and adjusted throughout therapy.
Use of the drug is not recommended in children under 5 years of age.
Patients with hepatic and renal impairment
In patients with impaired renal function, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with impaired hepatic function, the plasma concentration of the free fraction of risperidone is increased.
Regardless of the indication, these patients should receive half the initial and maintenance doses; dose titration should be slower.
The drug should be used with caution in this patient population.
Method of Administration
The drug is intended for oral administration. Food intake does not affect drug absorption.
At the end of treatment, gradual discontinuation of the drug is recommended. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia, have been observed after abrupt discontinuation of high doses of antipsychotic drugs (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 therapy with other drugs should be gradually discontinued during risperidone treatment. When switching from antipsychotic agents in "depot" form, risperidone therapy should be initiated instead of the next scheduled injection. The need for continuing current antiparkinsonian therapy should be periodically evaluated.
Children. Risperidone is indicated for the treatment of severe aggression in behavioral disorders in children aged 5 years and older.
Overdose.
Symptoms. Signs and symptoms observed in overdose are known adverse reactions to 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 fibrillation/flutter associated with risperidone overdose in combination with paroxetine has been reported.
In cases of acute overdose, the possibility of ingestion of multiple medicinal products should be considered.
Treatment. Airway patency should be ensured and maintained to provide adequate ventilation and oxygenation. Administration of activated charcoal together with a laxative should be considered no later than one hour after 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 employed. In cases of acute overdose, potential drug interactions involving multiple agents should be analyzed. Arterial hypotension and vascular collapse should be treated with measures such as intravenous fluid administration and/or sympathomimetic agents. In the event of acute extrapyramidal symptoms, anticholinergic agents should be administered. Continuous medical observation should be maintained until full 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 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, hyperinsulinemia, 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 |
tardive dyskinesia, cerebral ischemia, unresponsiveness, loss of consciousness, depressed level of consciousness, seizures, syncope, psychomotor hyperactivity, balance disorders, coordination disturbances, 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, hot flushes |
| Rare |
pulmonary embolism, venous thrombosis |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening airway patency, wheezing, stridor, dysphonia, respiratory disorders |
| Rare |
sleep apnea syndrome, hyperventilation |
| Gastrointestinal disorders |
|
| Common |
abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache |
| Uncommon |
fecal incontinence, fecal impaction, gastroenteritis, dysphagia, abdominal distension |
| Rare |
pancreatitis, gastrointestinal obstruction, tongue swelling, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
elevated transaminases, elevated γ-glutamyl transferase, elevated liver enzymes |
| Rare |
jaundice |
| Skin and subcutaneous tissue disorders |
|
| Common |
rash, erythema |
| Uncommon |
urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin color changes, acne, seborrheic dermatitis, skin disorders, skin injury |
| Rare |
drug rash, dandruff |
| Very rare |
angioedema |
| Not known |
Stevens-Johnson syndrome/toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders |
|
| Common |
muscle spasms, musculoskeletal pain, back pain, arthralgia |
| Uncommon |
increased creatine phosphokinase, posture abnormalities, joint stiffness, joint swelling, muscle weakness, neck pain |
| Rare |
rhabdomyolysis |
| Renal and urinary disorders |
|
| Common |
urinary incontinence |
| Uncommon |
pollakiuria, 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 disturbance, gynecomastia, galactorrhea, sexual dysfunction, breast pain, vaginal discharge |
| Rare |
priapism, menstrual delay, breast engorgement, breast enlargement, breast discharge |
| General disorders |
|
| Common |
edema, fever, chest pain, asthenia, fatigue, pain |
| Uncommon |
facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, hot flushes, 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, anovulation, galactorrhea, impaired fertility, decreased libido, and erectile dysfunction.
b During placebo-controlled studies, diabetes mellitus was reported in 0.18% of patients receiving risperidone, compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients 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, sialorrhea, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like face, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, myoclonus), and dystonia.
Dystonia includes dystonia, hypertonia, torticollis, involuntary muscle contractions, myogenic contractures, blepharospasm, eye movement disorders, tongue paralysis, tic (in the facial area), laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, trismus. A broader list of symptoms is included, not necessarily of extrapyramidal origin. Insomnia includes difficulty falling asleep, intrasomnic disturbances. Seizures include generalized tonic-clonic seizures. Menstrual disorders include irregular menstruation, oligomenorrhea. Edema includes generalized edema, peripheral edema, pitting edema.
Adverse reactions of paliperidone. Paliperidone is an active metabolite of risperidone; therefore, the adverse reaction profiles of these substances (including oral and injectable formulations) are similar. In addition to the adverse reactions listed above, postural orthostatic tachycardia syndrome has been reported with paliperidone use, which may also occur during risperidone treatment.
Adverse reactions common to antipsychotic medicinal products.
Prolongation of QT interval. As with other antipsychotics, QT interval prolongation has been reported during post-marketing use of risperidone. 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 atrial 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 risperidone versus placebo showing weight gain ≥7% in placebo-controlled trials lasting 6 to 8 weeks demonstrated a statistically significant difference in the frequency of weight gain in the risperidone group (18%) compared to the placebo group (9%). In 3-week placebo-controlled trials in adult patients with acute mania, the frequency of weight gain ≥7% was similar between the risperidone group (2.5%) and placebo group (2.4%), and slightly higher in the active control group (3.5%).
In pediatric populations with behavioral disorders, body weight increased on average by 7.3 kg after 12 months of treatment in long-term studies. The expected annual weight gain for children with normal body weight aged 5–12 years is 3 to 5 kg. Starting at age 12, girls continue to gain 3 to 5 kg per year, while boys gain on average 5 kg per year.
Additional information on specific patient categories. Adverse reactions reported more frequently in elderly patients with dementia or in children compared to adults are described below.
Elderly patients with dementia. Transient ischemic attack and cerebrovascular disorders were 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 fully studied (see section "Special precautions").
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. Tablets: No. 20 (10×2), No. 60 (10×6) in blisters in a carton.
Prescription status. Prescription only.
Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVTYA".
LIMITED LIABILITY COMPANY "FARMEKS GROUP".
Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenka Street, 22.
(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVTYA")
Ukraine, 08301, Kyiv region, Boryspil, Shevchenka Street, 100.
(LIMITED LIABILITY COMPANY "FARMEKS GROUP")