Risperidone-teva

INSTRUCTIONS for medical use of the medicinal product Risperidone-Teva (Risperidone-Teva)

Composition:

Active substance: risperidone;

One film-coated tablet contains risperidone 2 mg or 4 mg;

Excipients: core: lactose monohydrate, sodium lauryl sulfate, colloidal silicon dioxide anhydrous, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate (type A), magnesium stearate;

film coating: hypromellose, titanium dioxide (E 171), macrogol 6000, macrogol 400, iron oxide yellow (E 172); 2 mg tablets — iron oxide red (E 172); 4 mg tablets — quinoline yellow (E 104), indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

2 mg film-coated tablets: brown, round, slightly convex tablets with a diameter of approximately 8 mm and a thickness of approximately 3.5 mm, embossed with "RIS 2" and a break line on one side and a break line on the other side;

4 mg film-coated tablets: green, round, slightly convex tablets with a diameter of approximately 10.5 mm and a thickness of approximately 4.5 mm, embossed with "RIS 4" and a break line on one side and a break line on the other side.

Pharmacotherapeutic group. Agents acting on the nervous system. Psycholeptics.

Antipsychotics. Risperidone. ATC code N05AX08.

Pharmacological Properties.

Pharmacodynamics

Mechanism of action. 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 has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser extent compared to classical antipsychotics. The balanced central antagonism of 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 has the same pharmacological activity as risperidone.

Absorption. After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1–2 hours; in elderly patients, within 2–3 hours. The absolute bioavailability of risperidone after oral administration is 70% (CV = 25%). The relative bioavailability of oral risperidone in tablet form is 94% (CV = 10%) compared to the oral solution. Food does not affect absorption; therefore, risperidone can be administered regardless of food intake. Absolute bioavailability is 66% in fast metabolizers and 82% in slow metabolizers.

Distribution. Risperidone is rapidly distributed throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. Plasma protein binding of risperidone is 90%, and that of 9-hydroxyrisperidone is 77%.

In most patients, steady-state concentrations of risperidone are achieved within 1 day, and steady-state concentrations of 9-hydroxyrisperidone are achieved within 4–5 days of treatment.

Biotransformation and elimination. Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to that of risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. The CYP2D6 enzyme 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. Despite lower risperidone concentrations and higher 9-hydroxyrisperidone concentrations observed in fast metabolizers compared to slow metabolizers, the pharmacokinetics of the combination of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both fast and slow CYP2D6 metabolizers. Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. One week after administration, 70% of the dose is excreted in urine and 14% in feces. The total urinary excretion of risperidone and 9-hydroxyrisperidone 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 elimination half-life of 9-hydroxyrisperidone and the active antipsychotic fraction is 24 hours, and in elderly patients, 34 hours.

Linearity/Non-linearity. Plasma concentrations of risperidone are proportional to the dose within the therapeutic range.

Elderly patients, patients with hepatic or renal impairment. Pharmacokinetic studies after single oral doses of risperidone demonstrated in elderly patients a 43% higher plasma concentration of the active antipsychotic fraction, a 38% prolongation of elimination half-life, and a 30% reduction in clearance of the active antipsychotic fraction. In adult patients with renal impairment, 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 younger adults, 24.9 hours in adults with moderate renal impairment (~1.5 times longer than in younger adults), and 28.8 hours in adults with severe renal impairment (~1.7 times longer than in younger adults). Plasma concentrations of risperidone were within normal ranges in patients with hepatic impairment; however, the mean level of free (unbound) risperidone in plasma increased by 37.1%. Clearance and elimination half-life of risperidone and the active antipsychotic fraction after oral administration in adults with moderate to severe hepatic impairment did not differ significantly from those in healthy young adults.

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 revealed no significant influence of gender, race, or smoking on the pharmacokinetics of risperidone or the active antipsychotic fraction.

Clinical characteristics.

Indications.

• Treatment of schizophrenia;
• treatment of moderate to severe manic episodes associated with 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 risperidone be prescribed by a specialist in child 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 medicinal product. Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances). Dementia and suspected dementia with Lewy bodies (in addition to dementia symptoms, at least two of the following: parkinsonism, visual hallucinations, gait instability).

Interaction with other medicinal products and other types of interactions.

Pharmacodynamic interactions

Medicinal products capable of prolonging the QT interval. As with other antipsychotics, risperidone should be used with caution when administered concomitantly with medicinal products that prolong the QT interval, particularly antiarrhythmic agents (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, certain antimalarial agents (quinine and mefloquine), as well as medicinal products causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or agents that inhibit hepatic metabolism of risperidone. This list is indicative and not exhaustive.

Central-acting agents and alcohol. Due to an increased risk of sedative effects, risperidone should be used with caution in combination with other central-acting agents, particularly alcohol, opioids, antihistamines, and benzodiazepines.

Levodopa and dopamine agonists. Risperidone may exert antagonistic effects on levodopa and other dopamine agonists. If such combination is considered necessary, especially in the terminal stage of Parkinson's disease, the lowest effective dose of each drug should be prescribed.

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

Psychostimulant medicinal products. When psychostimulants (e.g., methylphenidate) are used concomitantly with risperidone, extrapyramidal symptoms may occur during dose adjustments of one or both agents (see section "Special precautions").

Paliperidone. Concomitant use of oral risperidone with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone and combination of these agents may result in excessive total exposure to the active antipsychotic fraction.

Pharmacokinetic interactions

Food does not affect the absorption of risperidone. Risperidone is predominantly metabolized by cytochrome CYP2D6 and to a lesser extent by CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that alter CYP2D6 activity, or potent inhibitors or inducers of CYP3A4 and/or P-gp, may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.

Potent CYP2D6 inhibitors. Concomitant use of risperidone with potent CYP2D6 inhibitors may increase plasma concentrations of risperidone, but less so than the concentration of the active antipsychotic fraction. When high doses of a potent CYP2D6 inhibitor are used, an increase in the concentration of the active antipsychotic fraction of risperidone may occur (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are expected to have a similar effect on risperidone plasma concentration. At the beginning or during discontinuation of concomitant use of paroxetine, quinidine, or another potent CYP2D6 inhibitor, especially at high doses, the physician should reconsider the dose of risperidone.

Inhibitors of CYP3A4 and/or 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 beginning or upon discontinuation of concomitant use of itraconazole or another potent inhibitor of CYP3A4 and/or P-gp, the physician should reconsider the dose of risperidone.

Inducers of CYP3A4 and/or 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 or upon discontinuation of concomitant use of carbamazepine or other potent inducers of CYP3A4 and/or P-gp, the physician should reconsider the dose of risperidone. The effect of CYP3A4 inducers develops over time, with maximum effect occurring at least 2 weeks after initiation of treatment. Similarly, after discontinuation of treatment, CYP3A4 induction may persist for at least 2 weeks.

Medicinal products with high plasma 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 concomitant use of medicinal products is required, the prescribing information regarding metabolic pathways and potential need for dose adjustment should be consulted.

Children. Interaction studies have been conducted only in adults. The relevance of results obtained in such studies for pediatric patients is unknown.

When psychostimulants (e.g., methylphenidate) are used concomitantly with risperidone, the pharmacokinetics and efficacy of risperidone in children and adolescents were not altered.

Examples. Below are examples of medicinal products that may potentially interact with risperidone or for which absence of interaction has been demonstrated.

Effect of other medicinal products on the pharmacokinetics of risperidone

Antibacterial agents. Erythromycin, a moderate inhibitor of CYP3A4 and inhibitor of P-gp, does not alter the pharmacokinetics of risperidone or its active antipsychotic fraction. Rifampicin, a potent inducer of CYP3A4 and P-gp inducer, reduces plasma concentrations of the active antipsychotic fraction.

Anticholinesterase agents. Donepezil and galantamine, substrates of CYP2D6 and CYP3A4, do not have a clinically significant effect on the pharmacokinetics of risperidone or the active antipsychotic fraction.

Antiepileptic agents. Carbamazepine, a potent inducer of CYP3A4 and P-gp, reduces plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may be observed with phenytoin and phenobarbital, which are also inducers of the hepatic enzyme CYP3A4 and P-gp. Topiramate moderately reduces the bioavailability of risperidone but does not affect the bioavailability of the active antipsychotic fraction. Therefore, this interaction is unlikely to be clinically significant.

Antifungal agents. Itraconazole, a potent inhibitor of CYP3A4 and P-gp inhibitor, at a dose of 200 mg/day increases plasma concentrations of the active antipsychotic fraction of risperidone (administered at 2–8 mg/day) by approximately 70%. Ketoconazole, a potent inhibitor of CYP3A4 and P-gp inhibitor, at a dose of 200 mg/day increases plasma concentrations of risperidone and decreases concentrations of 9-hydroxyrisperidone.

Antipsychotic agents. Phenothiazines may increase plasma concentrations of risperidone but do not affect concentrations of the active antipsychotic fraction.

Antiviral agents. Protease inhibitors: official study data are lacking; however, since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and ritonavir-boosted protease inhibitors may potentially increase plasma concentrations of the active antipsychotic fraction of risperidone.

β-blockers. Certain β-blockers may increase plasma concentrations of risperidone without affecting concentrations of the active antipsychotic fraction.

Calcium channel blockers. Verapamil, a moderate inhibitor of CYP3A4 and P-gp inhibitor, increases plasma concentrations of risperidone and the active antipsychotic fraction.

Agents for gastrointestinal disorders. H2-receptor antagonists: cimetidine and ranitidine, weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone and slightly increase the bioavailability of the active antipsychotic fraction.

SSRIs and tricyclic antidepressants. Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone but less so 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/day less so than the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase plasma concentrations of the active antipsychotic fraction of risperidone.

Tricyclic antidepressants may increase plasma concentrations of risperidone but do not affect concentrations 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/day are not associated with clinically significant changes in plasma concentrations of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg/day may increase plasma concentrations of the active antipsychotic fraction of risperidone.

Effect of risperidone on the pharmacokinetics of other medicinal products

Antiepileptic agents. Risperidone did not demonstrate a clinically significant effect on the pharmacokinetics of valproate or topiramate.

Antipsychotic agents. Aripiprazole, a substrate of CYP2D6 and CYP3A4: risperidone in tablet or injectable form does not affect the overall pharmacokinetics of aripiprazole and its active metabolite dehydroaripiprazole.

Cardiac glycosides. Risperidone did not demonstrate a clinically significant effect on the pharmacokinetics of digoxin.

Lithium. Risperidone did not demonstrate a clinically significant effect on the pharmacokinetics of lithium.

Concomitant use of risperidone with furosemide

For increased mortality in elderly patients with dementia receiving furosemide concomitantly, see section "Special precautions".

Special precautions for use.

Elderly patients with dementia

Increased mortality in elderly patients with dementia. A meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone, demonstrated an increased risk of mortality in elderly patients with dementia treated with atypical antipsychotics compared to those receiving placebo. In placebo-controlled trials using oral risperidone in this patient population, the incidence of death was 4.0% among patients treated with risperidone and 3.1% among those in the placebo group. The odds ratio (95% exact confidence interval) was 1.21 (0.7; 2.1). The mean age of patients who died was 86 years (range 67–100 years). Results from two large observational studies also showed a slightly increased risk of mortality in elderly patients with dementia treated with conventional (typical) antipsychotics compared to untreated individuals. 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 placebo-controlled trials of risperidone in elderly patients with dementia, an increased incidence of death was observed among patients receiving both furosemide and risperidone (7.3%; mean age 89 years, range 75–97 years) compared to those 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 concomitantly with furosemide and risperidone was observed in two out of four clinical trials. Concomitant use of risperidone with other diuretics was not associated with similar outcomes.

No pathophysiological mechanisms have been established to explain this observation. The cause of death was not uniform. Nevertheless, caution should be exercised, and the benefit-risk balance should be carefully evaluated before initiating this combination or concomitant therapy with other potent diuretics. Mortality was not increased in patients taking other diuretics concomitantly with risperidone. Regardless of treatment, dehydration was a common risk factor for fatal outcomes, and its occurrence should be carefully prevented in elderly patients with dementia.

Cerebrovascular adverse reactions (CVAE). In placebo-controlled clinical trials, elderly patients with dementia treated with risperidone experienced a higher incidence (approximately three times higher) of cerebrovascular adverse events (strokes and transient ischemic attacks), including fatal outcomes, compared to those receiving placebo (mean age 85 years; range 73–97 years).

Pooled data from six placebo-controlled risperidone 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 receiving risperidone therapy compared to 1.2% (8/712) in the placebo group. The relative risk between risperidone and placebo groups (odds ratio; 95% CI) was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk cannot be ruled out with other antipsychotics or in other patient populations. Risperidone should be used with caution in patients with risk factors for stroke.

The risk of CVAE was significantly higher in patients with mixed or vascular dementia than in those with Alzheimer's dementia. Therefore, risperidone should not be prescribed to patients with dementia types other than Alzheimer's dementia. A benefit-risk assessment is recommended when considering risperidone use in elderly patients with dementia, particularly regarding stroke risk. Patients and caregivers should be informed to promptly report any signs or symptoms suggestive of potential cerebrovascular disorders, such as sudden weakness or numbness of the face, arms, or legs, or speech or vision disturbances. Immediate evaluation of all treatment options, including discontinuation of risperidone, should be considered.

For the treatment of persistent aggression in patients with moderate to severe Alzheimer's dementia, risperidone should be used only short-term, as an adjunct to non-pharmacological interventions that have proven ineffective or have limited efficacy, or when there is a risk of harm to self or others. The patient's condition and need for continued therapy should be regularly reassessed.

Orthostatic hypotension. Orthostatic hypotension due to the α1-blocking effect of risperidone may occur, particularly at the beginning of treatment. Clinically significant hypotension has been reported during the post-marketing period with concomitant use of risperidone and 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 disease), and dose titration should be performed gradually according to recommendations (see section "Dosage and administration"). If hypotension occurs, dose reduction should be considered.

Leukopenia, neutropenia, and agranulocytosis. Cases of leukopenia, neutropenia, and agranulocytosis have been reported during treatment with antipsychotics, including risperidone. Agranulocytosis was reported very rarely during the post-marketing period (< 1/10,000 patients). Patients with a history of clinically significant leukopenia or drug-induced leukopenia/neutropenia should be monitored closely during the first few months of therapy. If significant leukopenia occurs without other identifiable causes, discontinuation of risperidone should be considered.

Careful monitoring is required in patients with clinically significant neutropenia for signs of fever or other symptoms or signs of infection, and appropriate treatment should be initiated immediately if such symptoms occur. In cases of severe neutropenia (absolute neutrophil count < 1 × 10⁹/L), risperidone therapy should be discontinued, and leukocyte counts should be monitored until values normalize.

Tardive dyskinesia/extrapyramidal symptoms. Medicinal products with dopamine receptor antagonist properties have been associated with tardive dyskinesia, characterized by involuntary rhythmic movements, predominantly of the tongue and/or face. 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 administering risperidone concomitantly with psychostimulants (e.g., methylphenidate), due to the potential emergence of extrapyramidal symptoms during dose titration of either or both agents. Discontinuation of psychostimulant therapy should be gradual (see section "Interaction with other medicinal products and other forms of interaction").

Malignant neuroleptic syndrome. Cases of malignant neuroleptic syndrome have been reported with antipsychotic treatment, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If malignant neuroleptic syndrome develops, all antipsychotics, including risperidone, should be discontinued.

Parkinson's disease and dementia with Lewy bodies. When prescribing antipsychotics, including risperidone, to patients with Parkinson's disease or dementia with Lewy bodies, physicians must carefully weigh the risks and expected benefits. Risperidone may worsen the course of Parkinson's disease. Patients with these conditions have an increased risk of developing malignant neuroleptic syndrome and heightened sensitivity to antipsychotics (e.g., confusion, sedation, and postural instability with frequent falls).

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, pre-existing obesity, a potential risk factor for these events, was noted. These events have very rarely been associated with ketoacidosis and rarely with diabetic coma. Therefore, appropriate clinical monitoring according to current guidelines for antipsychotic use is recommended. Patients receiving any atypical antipsychotic, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should undergo regular monitoring for potential deterioration in glucose control.

Weight gain. Significant weight gain has been reported with risperidone use. Regular monitoring of body weight is recommended.

Hyperprolactinemia. Hyperprolactinemia is a common adverse effect associated with risperidone treatment. Patients exhibiting signs of possible prolactin-related adverse effects (e.g., gynecomastia, menstrual disorders, anovulation, fertility impairment, decreased libido, erectile dysfunction, galactorrhea) should have plasma prolactin levels monitored.

In vitro tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although clinical and epidemiological studies have not demonstrated a clear association with antipsychotic use, caution is advised when prescribing to patients with relevant medical history. Risperidone should be used cautiously in patients with existing hyperprolactinemia or prolactin-dependent tumors.

QT interval prolongation. Very rare cases of QT interval prolongation have been reported during the post-marketing period. As with other antipsychotics, risperidone should be used cautiously in patients with known cardiovascular disorders, family history of QT prolongation, bradycardia, or electrolyte imbalance (hypokalemia, hypomagnesemia), due to the potential risk of arrhythmogenic reactions. Caution is also required when risperidone is used concomitantly with drugs known to prolong the QT interval.

Seizures. Risperidone should be used with caution in patients with a history of seizures or other conditions that may lower the seizure threshold.

Priapism. Priapism may occur with risperidone use due to its α-adrenergic blocking effect.

Body temperature regulation. Antipsychotic medicinal products may impair the body's ability to reduce core body temperature. Appropriate monitoring is recommended for patients treated with risperidone who may be exposed to factors that increase core body temperature, such as strenuous physical activity, high ambient temperatures, concomitant use of anticholinergic drugs, or dehydration.

Anti-emetic effect. Preclinical studies of risperidone have shown an anti-emetic effect. This effect may mask signs and symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, or brain tumors.

Renal and hepatic function impairment. In patients with impaired renal function, the ability to eliminate the active antipsychotic fraction is reduced compared to adults with normal renal function. In patients with hepatic impairment, the plasma concentration of the free fraction of risperidone is increased (see section "Dosage and administration").

Venous thromboembolism (VTE). Cases of venous thromboembolism (VTE) have been reported with antipsychotic use. Since patients undergoing antipsychotic therapy often have acquired risk factors for VTE, all potential VTE risk factors should be identified before and during risperidone treatment, and appropriate preventive measures should be taken.

Intraoperative floppy iris syndrome (IFIS). IFIS has been observed during cataract surgery in patients receiving α1-adrenergic receptor antagonists, including risperidone. This syndrome may increase the risk of ocular complications during and after surgery. The ophthalmic surgeon should be informed before surgery about any current or previous use of antipsychotic medicinal products. The potential benefit of discontinuing α1-adrenergic blockers before cataract surgery has not been established and should be weighed against the risks associated with discontinuing antipsychotic therapy.

Children. A comprehensive evaluation for possible physical and social causes of aggressive behavior (e.g., pain or inappropriate environmental demands) should be performed before initiating risperidone in children or adolescents with behavioral disorders.

Sedative effects of risperidone should be carefully monitored in this patient group due to potential impact on learning ability. Adjusting the time of administration may help reduce the sedative effect on attention in children and adolescents. Risperidone has been associated with increased body weight and body mass index (BMI). Body weight should be measured before starting treatment and monitored regularly thereafter. Growth changes observed in long-term open-label extension studies were within the normal age range. The effect of long-term risperidone therapy on sexual development and final height has not been adequately studied.

Due to the potential impact of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, periodic clinical assessment of endocrine status in pediatric patients should be considered, including monitoring of height, weight, sexual development, menstrual cycle, and other prolactin-related effects.

Results from a small post-marketing observational study showed that patients aged 8 to 16 years receiving risperidone were on average 3.0–4.8 cm taller than those treated with other antipsychotics. However, the data were insufficient to determine whether risperidone use affects final adult height, or whether the observed results were due to a direct effect of risperidone on bone growth, the underlying disease, or improved control of the primary condition leading to increased linear growth. Regular monitoring for extrapyramidal symptoms and other movement disorders should also be performed during risperidone treatment. Specific dosing recommendations for children and adolescents are provided in the section "Dosage and administration."

Excipients

Lactose. Patients with rare hereditary disorders such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet and is therefore considered sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of risperidone in pregnant women are insufficient. Animal studies did not demonstrate teratogenic effects of risperidone, but other forms of reproductive toxicity were observed. The potential risk in humans is unknown.

Newborns whose mothers took antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of developing extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration. Symptoms reported include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. Therefore, such newborns require careful monitoring. Risperidone should not be used during pregnancy except in cases of extreme necessity. If discontinuation of treatment during pregnancy is required, it should not be done abruptly.

Breastfeeding. Risperidone and 9-hydroxyrisperidone were excreted in breast milk in animal studies. It has also been established that risperidone and 9-hydroxyrisperidone are excreted in human breast milk in small amounts. Data on adverse reactions in breastfed infants are lacking. Therefore, the benefits of breastfeeding should be weighed against the potential risks to the infant.

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, in turn, may inhibit reproductive function by disrupting gonadal steroidogenesis in both women and men.

These effects were not observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

Due to potential effects on the nervous system and visual organs, risperidone may have a slight or moderate influence on the ability to drive vehicles or operate machinery (see section "Adverse reactions"). Therefore, patients should be advised to refrain from driving or operating machinery until their individual response to the drug is known.

Method of Administration and Dosage

The Risperidone-Teva tablet can be divided into two equal doses.

Dosage

Schizophrenia

Adults. Risperidone-Teva is administered once or twice daily.

Treatment should be initiated at a dose of 2 mg per day. On the second day of treatment, the dose may be increased to 4 mg. After this, the dose may be maintained unchanged or, if necessary, continued individual dose titration may be performed. For most patients, effective daily doses range from 4 to 6 mg. Some patients may require a longer dose titration phase and lower initial and maintenance doses.

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

The safety of doses exceeding 16 mg per day has not been studied; therefore, the use of the drug at such doses is not recommended.

Elderly patients (aged 65 years and older). The recommended initial dose is 0.5 mg twice daily. Individual dose adjustment is permitted, increasing by 0.5 mg twice daily until reaching a dose of 1–2 mg twice daily.

Children. Due to lack of efficacy data, risperidone is not recommended for children and adolescents (under 18 years of age) with schizophrenia.

Manic Episodes in Bipolar Disorder

Adults. Risperidone is administered once daily, starting at 2 mg. Dose adjustments, if needed, should be performed at intervals of at least 24 hours, increasing the dose by 1 mg per day. Doses ranging from 1 to 6 mg per day may be used to optimize efficacy and tolerability for each patient. The use of risperidone at daily doses exceeding 6 mg has not been studied in patients with manic episodes. As with other symptomatic treatments, the need for and appropriateness of continuing risperidone therapy should be periodically evaluated.

Elderly patients (aged 65 years and older). The recommended initial dose is 0.5 mg twice daily. Individual dose adjustment is permitted, increasing by 0.5 mg twice daily until reaching a dose of 1–2 mg twice daily. Due to limited clinical experience with the drug in elderly patients, treatment in this population requires caution.

Children. Due to lack of efficacy data, risperidone is not recommended for children and adolescents (under 18 years of age) with bipolar mania.

Short-term Treatment of Severe Aggression in Patients with Alzheimer's Type Dementia

The recommended initial dose is 0.25 mg twice daily. For administration of the 0.25 mg dose, the recommended dosage form is risperidone oral solution 1 mg/mL. This dose may be individually increased by 0.25 mg twice daily, with dose increases performed, if necessary, no more frequently than every other day. The optimal dose for most patients is 0.5 mg twice daily. However, some patients may require doses up to 1 mg twice daily to achieve a beneficial effect.

The use of risperidone for longer than 6 weeks is not recommended in patients with persistent aggression associated with Alzheimer's dementia. Careful monitoring of patients is required during treatment, and the need for continued therapy should be regularly assessed.

Short-term Symptomatic Treatment (up to 6 weeks) of Severe Aggression in Behavioral Disorders

Children and Adolescents Aged 5 to 18 Years

For patients with body weight ≥ 50 kg, the recommended initial dose is 0.5 mg of the drug once daily. If needed, individual dose adjustment may be performed by increasing the dose by 0.5 mg once daily, but no more frequently than every other day. For most patients, the optimal dose is 1 mg once daily. However, efficacy may be observed at a dose of 0.5 mg once daily in some patients, while others may require a dose of 1.5 mg once daily.

For patients with body weight < 50 kg, the recommended initial dose is 0.25 mg once daily. The oral solution 1 mg/mL is the recommended dosage form for administering the 0.25 mg dose. If needed, individual dose adjustment may be performed by increasing the dose by 0.25 mg once daily, but no more frequently than every other day. For most patients, the optimal dose is 0.5 mg once daily. However, efficacy may be observed at a dose of 0.25 mg once daily in some patients, while others may require 0.75 mg once daily. The oral solution risperidone 1 mg/mL is the recommended dosage form for administering the 0.75 mg dose.

As with other symptomatic treatments, the need for and appropriateness of continuing risperidone therapy should be periodically evaluated.

Due to lack of experience with risperidone in children under 5 years of age with the mentioned disorders, the drug is not recommended for patients in this category.

Patients with Renal or Hepatic Impairment

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

Regardless of the indication, initial and subsequent doses for patients with renal or hepatic impairment should be halved, and dose titration should proceed at a slower pace. Risperidone should be used with caution in these patient populations.

Method of Administration

Film-coated tablets are intended for oral administration. Food intake does not affect the absorption of risperidone.

Discontinuation of treatment should be performed gradually. Very rarely, abrupt discontinuation of high-dose antipsychotic therapy has been associated with acute withdrawal symptoms, including nausea, vomiting, excessive sweating, and insomnia (see section "Adverse Reactions"). Additionally, relapse of psychotic symptoms and involuntary movement disorders (such as akathisia, dystonia, and dyskinesia) may occur.

Switching from Other Antipsychotic Medications

If clinically justified, it is recommended to gradually discontinue prior antipsychotic therapy 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 concomitant anti-Parkinsonian medication should be periodically evaluated.

Children.

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

Overdose.

Symptoms. Signs and symptoms observed in overdose are generally consistent with the known pharmacological effects of risperidone, manifested in an exaggerated form. These include somnolence and sedation, tachycardia, hypotension, and extrapyramidal symptoms. QT interval prolongation and seizures have also been reported. Polymorphic ventricular tachycardia of the "torsades de pointes" type has been reported in association with concomitant overdose of risperidone and paroxetine. In cases of acute overdose, the possibility of multiple drug ingestion should be considered.

Treatment. Airway patency should be ensured and maintained to support adequate oxygenation and ventilation. Administration of activated charcoal with a laxative may be beneficial if less than 1 hour has passed since drug ingestion. Immediate cardiovascular monitoring, including continuous ECG monitoring to detect possible arrhythmias, should be initiated.

There is no specific antidote for risperidone. Therefore, appropriate supportive measures should be implemented. In cases of acute overdose, potential drug interactions involving multiple agents should be evaluated. For hypotension and vascular collapse, appropriate treatment with intravenous fluids and/or sympathomimetic agents should be administered. Anticholinergic agents should be prescribed for pronounced extrapyramidal symptoms. The patient should remain under close medical supervision and monitoring until full recovery.

Side effects

The most commonly reported side effects of the drug (frequency ≥ 10%) were parkinsonism, sedative effect/somnolence, headache, and insomnia. Parkinsonism and akathisia are dose-dependent side effects.

Below is a list of all side effects observed during clinical trials and post-marketing use of risperidone. Frequencies are based on data from clinical trials. The following frequency categories are used: 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 frequency not known (cannot be estimated from available data).

Within each group, side effects 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, local infections, viral infections, acarodermatitis. Rare: infections.

Blood and lymphatic system disorders. Uncommon: neutropenia, decreased white blood cell count, thrombocytopenia, anemia, decreased hematocrit, increased eosinophil count. Rare: agranulocytosis^c.

Immune system disorders. Uncommon: hypersensitivity. Rare: anaphylactic reactions^c.

Endocrine disorders. Common: hyperprolactinaemia^a. Rare: disorders of antidiuretic hormone secretion, glucosuria.

Metabolism and nutrition disorders. Common: weight gain, increased appetite, decreased appetite. Uncommon: diabetes mellitus^b, hyperglycaemia, polydipsia, weight loss, anorexia, increased blood cholesterol. Rare: water intoxication^c, hypoglycaemia, hyperinsulinaemia^c, increased blood triglycerides. Very rare: diabetic ketoacidosis.

Psychiatric disorders. Very common: insomnia^d. Common: sleep disorders, agitation, depression, anxiety. Uncommon: mania, confusion, decreased libido, restlessness, nightmares. Rare: catatonia, sleepwalking, sleep-related eating disorders, blunted affect, anorgasmia.

Nervous system disorders. Very common: sedation/somnolence, parkinsonism^d, headache. Common: akathisia^d, dystonia^d, dizziness, dyskinesia^d, tremor. Uncommon: tardive dyskinesia, cerebral ischaemia, lack of response to stimuli, loss of consciousness, decreased level of consciousness, seizures^d, syncope, psychomotor hyperactivity, balance disorder, coordination disorder, postural dizziness, attention disorders, dysarthria, dysgeusia, hypoesthesia, paraesthesia. Rare: neuroleptic malignant syndrome, cerebrovascular disorders, diabetic coma, rhythmic head bobbing.

Eye disorders. Common: blurred vision, conjunctivitis. Uncommon: photophobia, dry eyes, increased lacrimation, ocular hyperaemia. Rare: glaucoma, eye movement disorders, rolling of eyes, eyelid margin crusting, intraoperative floppy-iris syndrome^c.

Ear and labyrinth disorders. Uncommon: vertigo, tinnitus, ear pain.

Cardiac disorders. Common: tachycardia. Uncommon: atrial fibrillation, atrioventricular block, conduction disorders, QT interval prolongation on ECG, bradycardia, electrocardiogram abnormalities, palpitations. Rare: sinus arrhythmia.

Vascular disorders. Common: hypertension. Uncommon: hypotension, orthostatic hypotension, flushing. Rare: pulmonary embolism, venous thrombosis.

Respiratory, thoracic and mediastinal disorders. Common: dyspnoea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion. Uncommon: aspiration pneumonia, pulmonary congestion, respiratory congestion, wheezing, stridor, dysphonia, respiratory disorders. Rare: sleep apnoea syndrome, hyperventilation.

Gastrointestinal disorders. Common: abdominal pain, discomfort in abdomen, vomiting, nausea, constipation, diarrhoea, dyspepsia, dry mouth, toothache. Uncommon: faecal incontinence, faecaloma, gastroenteritis, dysphagia, abdominal distension. Rare: pancreatitis, intestinal obstruction, tongue oedema, cheilitis. Very rare: ileus.

Hepatobiliary disorders. Uncommon: increased transaminases, increased gamma-glutamyl transferase, increased liver enzymes. Rare: jaundice.

Skin and subcutaneous tissue disorders. Common: rash, erythema. Uncommon: urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discoloration, acne, seborrhoeic dermatitis, skin disorders, skin injury. Rare: drug-induced dermatitis, dandruff. Very rare: angioedema. Frequency not known: Stevens-Johnson syndrome/toxic epidermal necrolysis^c.

Musculoskeletal and connective tissue disorders. Common: muscle spasms, musculoskeletal pain, back pain, arthralgia. Uncommon: increased blood creatine phosphokinase, abnormal posture, joint stiffness, joint swelling, muscle weakness, neck pain. Rare: rhabdomyolysis.

Renal and urinary disorders. Common: urinary incontinence. Uncommon: polyuria, urinary retention, dysuria.

Pregnancy, puerperium and perinatal conditions. Rare: drug withdrawal syndrome in newborns^c.

Reproductive system and breast disorders. Uncommon: erectile dysfunction, ejaculation disorder, amenorrhoea, menstrual disorders^d, gynaecomastia, galactorrhoea, sexual dysfunction, breast pain, breast discomfort, vaginal discharge. Rare: priapism^c, menstrual delay, breast induration, breast enlargement, breast discharge.

General disorders and administration site conditions. Common: oedema^d, pyrexia, chest pain, asthenia, fatigue, pain. Uncommon: facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, malaise, unusual feeling, discomfort. Rare: hypothermia, decreased body temperature, cold extremities, drug withdrawal syndrome, induration^c.

Injury, poisoning and procedural complications. Common: falls. Uncommon: procedural pain.

a Hyperprolactinaemia may in some cases lead to gynaecomastia, menstrual disorders, amenorrhoea, anovulation, galactorrhoea, fertility disorders, decreased libido, erectile dysfunction.

b In placebo-controlled studies, diabetes mellitus was observed in 0.18% of patients treated with risperidone and 0.11% of patients in the placebo group. The cumulative incidence across all clinical trials was 0.43% in patients receiving risperidone.

c Not observed in clinical trials, but reported during post-marketing use of risperidone.

d Possible extrapyramidal disorders: parkinsonism (hypersalivation, skeletal muscle rigidity, parkinsonism, drooling, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like face, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian resting tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle spasms, choreoathetosis, athetosis, myoclonus), dystonia. Dystonia includes: dystonia, hypertonia, torticollis, involuntary muscle contractions, muscle contractures, blepharospasm, eye movement disorders, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, trismus. Note that the list includes a broader range of symptoms, not all of which necessarily have an extrapyramidal origin. Insomnia includes difficulty falling asleep and intrasomnic disturbances. Seizures include grand mal epileptic seizures. Menstrual disorders include irregular menstruation and oligomenorrhoea. Oedema includes generalized oedema, peripheral oedema, pitting oedema.

Side effects observed with paliperidone

Paliperidone is the active metabolite of risperidone; therefore, the side effect profiles of these drugs (both oral and injectable forms) are similar. In addition to the side effects listed above, the following side effects have been observed with paliperidone-containing products and may also be expected during risperidone treatment.

Cardiac disorders. Postural orthostatic tachycardia syndrome.

Class-specific side effects. As with other antipsychotic drugs, very rare cases of QT interval prolongation have been reported during post-marketing use of risperidone. Other class-specific cardiac side effects observed with antipsychotics that prolong the QT interval include: ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and polymorphic ventricular tachycardia (torsades de pointes).

Venous thromboembolism. Venous thromboembolism, including pulmonary embolism and deep vein thrombosis, has been reported with antipsychotic drugs.

Weight gain. In placebo-controlled studies of 6 to 8 weeks' duration in adult patients with schizophrenia, a statistically significant difference in the incidence of weight gain ≥ 7% was observed in the risperidone group (18%) compared to the placebo group (9%). In 3-week placebo-controlled studies in adult patients with acute mania, the incidence of weight gain ≥ 7% at endpoint was comparable between the risperidone (2.5%) and placebo (2.4%) groups, but slightly higher in the active control group (3.5%).

In long-term studies in children and adolescents with behavioural disorders, an average weight gain of 7.3 kg was observed after 12 months of treatment. The expected annual weight gain in children aged 5–12 years with normal weight is 3–5 kg. From ages 12–16, this weight gain of 3–5 kg per year continues in girls, while boys gain approximately 5 kg per year.

Special patient groups

The following side effects were observed more frequently in elderly patients with dementia or in children than in adult patients.

Elderly patients with dementia. Among the side effects observed in clinical trials in elderly patients with dementia were transient ischaemic attack and stroke, with frequencies of 1.4% and 1.5%, respectively. In addition, the following side effects occurred with a frequency ≥ 5% in elderly patients with dementia, at least twice the rate observed in other adult patient groups: urinary tract infections, peripheral oedema, lethargy, and cough.

Children. Overall, the expected side effects in children are generally similar in type to those in adults. Adverse events observed in children (aged 5–17 years) with a frequency ≥ 5%, at least twice that observed in adult clinical trials, include: 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 on sexual maturation and growth has not been adequately studied (see section "Special precautions for use", subsection "Children").

Reporting suspected adverse reactions. Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister; 2, 3, 6, or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Teva Pharmaceutical Works Ltd. Co.

Manufacturer's address and place of business.

Unit 1; H-4042 Debrecen, Pallagi Street 13, Hungary.