Neurispan-zdorovya
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE 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 sparkle) containing potassium aluminosilicate, titanium dioxide (E 171); colouring agent: for 2 mg tablets – sunset yellow 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 colour with a pearly sheen; 2 mg tablets – yellowish-orange in colour with a pearly sheen; 4 mg tablets – light green in colour with a pearly sheen.
Pharmacotherapeutic group. Antipsychotic agents. ATC code N05AX08.
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 histaminergic H1 and α2-adrenergic receptors. Risperidone does not exhibit affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against the positive symptoms of schizophrenia, it causes less pronounced motor activity suppression and induces catalepsy to a lesser degree compared to classical neuroleptics. The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect to include negative and affective symptoms of schizophrenia.
Pharmacokinetics. Risperidone is metabolized to 9-hydroxyrisperidone, which 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 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% 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 exerts a pharmacological effect analogous to risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. Cytochrome CYP2D6 is subject to genetic polymorphism. In fast metabolizers, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, this conversion occurs much more slowly. Although plasma 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, it extends 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 in these patients, plasma levels of the active antipsychotic fraction are 43% higher, the elimination half-life is 38% longer, and clearance of the active antipsychotic fraction is 30% lower.
In adult patients with impaired renal function, clearance of the active fraction was ~48% of that in adults with normal renal function. In adult patients with severe renal impairment, clearance was ~31% of that in adults with normal renal function. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (approximately 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in young adults). In patients with hepatic insufficiency, plasma concentrations of risperidone were within normal ranges, but the mean value of the free fraction of risperidone in plasma was increased by 37.1%.
After oral administration, clearance and elimination half-life values of risperidone and the active antipsychotic fraction in patients with moderate to severe hepatic impairment did not differ significantly from those in young healthy volunteers.
Children. The pharmacokinetics of risperidone, 9-hydroxyrisperidone, and the active antipsychotic fraction in children are similar to those in adults.
Gender, race, and smoking. Population pharmacokinetic analysis did not reveal any significant influence of gender, age, or smoking habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Clinical characteristics.
Indications.
- Treatment of schizophrenia;
- treatment of moderate to severe manic episodes in bipolar disorders;
- short-term treatment (up to 6 weeks) of marked aggression in patients with moderate to severe Alzheimer's type dementia when there is a threat of harm to self or others and 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 aged 5 years and adolescents with below-average intellectual development or intellectual disability diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological treatment should be an integral part of a comprehensive treatment program including 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 substance or to any of the excipients 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 forms of interaction.
Pharmacodynamic interactions.
Medicinal products that prolong the QT interval. As with other antipsychotics, caution should be exercised when administering risperidone with medicinal products that prolong the QT interval, such as antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, 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 with caution in combination with other centrally acting substances, including alcohol, opioids, antihistamines, and benzodiazepines, due to an increased risk of sedation.
Levodopa and dopamine agonists. Risperidone may exhibit antagonistic effects to levodopa and other dopamine agonists. If such a combination is considered necessary, especially in the terminal stage of Parkinson's disease, the lowest effective doses of each drug should be prescribed.
Medicinal products with hypotensive effect. Clinically significant hypotension has been observed in the post-marketing period during 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 lead to an additive effect 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. When risperidone is used concomitantly with a potent CYP2D6 inhibitor, plasma concentrations of risperidone may increase, 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 initiation of concomitant therapy, and upon discontinuation of itraconazole or other potent inhibitors of CYP3A4 and/or P-glycoprotein, the physician should review the risperidone dose.
Inducers of CYP3A4 and P-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-gp, the physician should review the risperidone dose. The effect of CYP3A4 inducers depends on time, with maximum impact potentially reached at least 2 weeks after initiation of treatment. Accordingly, after discontinuation 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 the protein fraction has not been observed. When used concomitantly with such a medicinal product, refer to its instructions for medical use 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.
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 per day increases plasma concentrations of the active antipsychotic fraction by approximately 70% when used concomitantly with risperidone at doses of 2 to 8 mg per day.
- Ketoconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg per day 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 THE TREATMENT OF GASTROINTESTINAL DISORDERS
- H2-receptor antagonists: cimetidine and ranitidine, weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone and minimally affect the bioavailability of the active antipsychotic fraction.
SSRIs and tricyclic antidepressants
- Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but to a lesser extent than the concentration of the active antipsychotic fraction.
- Paroxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but (at doses up to 20 mg per day) to a lesser extent than the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction.
- Tricyclic antidepressants may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at doses up to 100 mg per day do not cause clinically significant changes in the concentration of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg per day 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. In a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone, a higher rate of mortality was observed in elderly patients with dementia treated with atypical antipsychotics compared to those in the placebo group. In a placebo-controlled trial using risperidone in these patients, 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 suggest that elderly patients with dementia treated with conventional (typical) antipsychotics have a slightly increased 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 only with risperidone (3.1%; mean age 84 years, range 70–96 years) or only with furosemide (4.1%; mean age 80 years, range 67–90 years). Increased mortality in patients treated concomitantly with risperidone and furosemide was observed in two out of four clinical trials. No increased mortality was observed in patients who received risperidone with other diuretics.
No pathophysiological mechanisms have been established to explain this observation. The cause of death was not uniform. However, particular caution should be exercised when prescribing this combination, and a risk-benefit assessment should be performed before initiating therapy, including combinations with other potential diuretics. No increased mortality was observed in patients who received risperidone with other diuretics. Dehydration, regardless of treatment, was a common risk factor for mortality and should be carefully monitored in patients with dementia.
Cerebrovascular adverse reactions. In placebo-controlled clinical trials, elderly patients with dementia treated with risperidone had 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) showed cerebrovascular disorders (serious and non-serious, combined) in 3.3% (33/1009) of patients treated with risperidone compared to 1.2% (8/712) of patients receiving placebo. The odds ratio (95% CI) between the risperidone and placebo groups was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk of cerebrovascular events cannot be ruled out for other antipsychotics or other patient groups. Risperidone should be used with caution in patients with risk factors for stroke.
The risk of cerebrovascular adverse 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.
A careful assessment of risks and benefits should be performed before prescribing risperidone to elderly patients with dementia, particularly considering the risk of stroke. 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 Alzheimer's disease of moderate to severe degree, 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 in the absence of 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, orthostatic hypotension may occur, especially 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 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 during the post-marketing period (<1/10,000 patients).
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 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 reported with drugs that act as dopamine receptor antagonists. The occurrence of extrapyramidal symptoms is a risk factor for developing 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 during dose adjustment of either or both agents. Gradual discontinuation of psychostimulant therapy is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Neuroleptic Malignant Syndrome (NMS). 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 NMS 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 may worsen the course of Parkinson’s disease. Patients with 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 exacerbation of pre-existing diabetes have been reported during treatment with risperidone.
In some cases, pre-existing obesity, which may be a triggering factor, was reported. Very rarely, ketoacidosis and, less frequently, diabetic coma have been reported. Appropriate clinical monitoring according to standard antipsychotic use guidelines is recommended. Patients taking any atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, weakness). Patients with diabetes should be regularly monitored for worsening glucose control.
Weight gain. Significant weight gain has been reported during treatment with risperidone. Regular monitoring of body weight is recommended.
Hyperprolactinemia. Hyperprolactinemia is a common side effect of risperidone treatment. Monitoring of prolactin levels is recommended in patients with side effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disturbances, decreased libido, erectile dysfunction, galactorrhea).
In vitro 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. The drug should be used cautiously in patients with hyperprolactinemia or prolactin-dependent tumors.
QT interval prolongation. QT interval prolongation has been reported very rarely during 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 advised when risperidone is used concomitantly with other drugs 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 potentially lower the seizure threshold.
Priapism. Priapism may occur during treatment with risperidone 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 increase core body temperature, such as intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic drugs, or dehydration.
Antiemetic effect. Preclinical studies have shown risperidone to have 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 impairment. Patients with impaired renal function have reduced clearance of the active antipsychotic fraction compared to adults with normal renal function. In patients with hepatic impairment, 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 drugs. 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 ocular surgical complications during and after the procedure. The ophthalmic surgeon should be informed of current or past antipsychotic use. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risks of discontinuing antipsychotic therapy should be weighed.
Children. Before prescribing risperidone to children or adolescents with behavioral disorders, a careful risk-benefit assessment should be performed, and physical and social causes of aggressive behavior (e.g., pain stimuli, inappropriate response to environment) should be evaluated.
The sedative effect of risperidone should be carefully monitored in pediatric patients due to potential effects on learning ability. Adjusting the time of 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 is recommended before starting treatment, with regular monitoring during therapy. Growth changes in long-term open-label extension studies were within expected age-related norms. The effect of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.
Due to the potential impact of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including measurements of height, 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 related to risperidone's effect on bone growth, whether the underlying disease influences bone growth, or whether the results reflect 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. The medicinal product contains lactose. If a patient has known intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.
The 2 mg tablets contain the colorant Yellow West FCF (E 110), which may cause allergic reactions.
Use during pregnancy or breastfeeding.
Pregnancy. Controlled studies in pregnant women have not been conducted. Although teratogenic effects were not observed in animal studies, other signs of reproductive toxicity were noted. The potential risk 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 muscle tone (increased or decreased), tremor, somnolence, respiratory disturbances, or feeding difficulties. The severity of these complications may vary. Therefore, newborns should be carefully monitored.
The drug is not recommended during pregnancy except in cases of life necessity. 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 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 reduced pituitary gonadotropin secretion. This may negatively affect reproductive function in both women and men due to impaired gonadal steroidogenesis.
No relevant effects were observed in preclinical studies.
Ability to affect reaction speed when driving or operating machinery. The drug may have a slight or moderate effect on the ability to drive due to its potential effects on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving or operating machinery until individual sensitivity to the drug is known.
Administration and Dosage
To obtain the prescribed doses of the medicinal product, risperidone medicinal forms with the appropriate content of active substance should be used.
Dosage
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, continued individual dose adjustment may be performed.
The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or a reduced initial and maintenance dose.
Doses exceeding 10 mg of risperidone per day have not demonstrated higher efficacy compared to lower doses, but they may cause extrapyramidal symptoms.
The safety of doses exceeding 16 mg per day has not been studied.
Elderly patients (aged 65 years and older). The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily.
Children. 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 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 when administering the drug.
Children. 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. 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 marked 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 marked 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 dose, and dose titration should be slower.
The drug should be used with caution in this patient population.
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. 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"). Relapse of psychotic symptoms may also occur, and cases of involuntary movements (e.g., akathisia, dystonia, and dyskinesia) have been reported.
Switching from therapy with other antipsychotics
If clinically justified, it is recommended to gradually discontinue previous therapy with other drugs when initiating risperidone treatment. When switching from depot antipsychotic formulations, risperidone therapy should be initiated instead of the next scheduled injection. The need for continuing current antiparkinsonian therapy should be periodically evaluated.
Children. Risperidone may be 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 known adverse reactions to the drug, manifested in an intensified form: somnolence and sedation, tachycardia and hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported in cases of overdose. Atrial flutter/fibrillation 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 with a laxative should be considered, if given 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 taken. In cases of acute overdose, potential drug interactions involving multiple agents should be analyzed. 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 frequently 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).
Within each category, adverse reactions are listed in order of decreasing severity.
| Infections and infestations |
|
| Common |
pneumonia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, ear infections, influenza |
| Uncommon |
respiratory tract infections, cystitis, eye infections, tonsillitis, onychomycosis, 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 eosinophil count |
| Rare |
agranulocytosis |
| Immune system disorders |
|
| Uncommon |
hypersensitivity |
| Rare |
anaphylactic reaction |
| Endocrine disorders |
|
| Common |
hyperprolactinemia |
| Rare |
antidiuretic hormone secretion disorder, 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 triglyceride level |
| 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, sleepwalking, 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, loss of consciousness, depressed level of consciousness, seizures, syncope, psychomotor hyperactivity, balance disorder, coordination impairment, postural dizziness, attention disturbance, 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, impaired eye movement, 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 disorder, 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, thoracic and mediastinal disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening airway patency, wheezing, stridor, dysphonia, respiratory disorders |
| Rare |
sleep apnea syndrome, hyperventilation |
| Gastrointestinal disorders |
|
| Common |
abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache |
| Uncommon |
fecal incontinence, fecaloma, gastroenteritis, dysphagia, abdominal distension |
| Rare |
pancreatitis, gastrointestinal obstruction, tongue swelling, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
elevated transaminase levels, elevated γ-glutamyl transferase levels, elevated liver enzyme levels |
| 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 disease, skin injury |
| Rare |
drug eruption, 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 |
elevated creatine phosphokinase level, posture abnormalities, 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 |
neonatal withdrawal syndrome |
| Reproductive system and breast disorders |
|
| Uncommon |
erectile dysfunction, ejaculation disorder, amenorrhea, menstrual cycle disorder, 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 |
post-surgical pain |
a Hyperprolactinaemia may in some cases lead to gynaecomastia, menstrual disorders, amenorrhoea, anovulation, galactorrhoea, impaired fertility, decreased libido, erectile dysfunction.
b During placebo-controlled trials, diabetes mellitus was reported in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence in all clinical trials was 0.43% among 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, sialorrhoea, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like facies, 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, glossoplegia, 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, oligomenorrhoea. 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 possibly occur with risperidone.
Adverse reactions common to antipsychotic medicinal products.
Prolongation of QT interval. As with other antipsychotics, QT interval prolongation has been reported during the post-marketing period with 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 of ≥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 in the risperidone group (2.5%) and the placebo group (2.4%), and slightly higher in the active comparator 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 weight gain for children with normal body weight aged 5–12 years is 3 to 5 kg per year. 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 on 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 ischaemic 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, adverse reactions reported in elderly patients with dementia at a frequency ≥5% and at least twice as high as in other adult patient groups include: 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, diarrhoea, 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 № 20 (10×2), № 60 (10×6) in blisters, in a carton.
Category of supply. Prescription only.
Manufacturer
Limited Liability Company "FARMEKS GROUP".
Manufacturer's address and location of business operations. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.
(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")
Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.
(LIMITED LIABILITY COMPANY "FARMEKS GROUP")