Risperidone-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Risperidone-Teva (Risperidone-Teva)

Composition:

active substance: risperidone;

1 ml of solution contains risperidone 1 mg;

excipients: benzoic acid (E 210), tartaric acid, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical characteristics: clear, colorless liquid without visible particles.

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05AX08.

Pharmacological properties.

Pharmacodynamics. Risperidone is a selective monoaminergic antagonist with unique properties. It exhibits high affinity for serotonergic 5-HT2 and dopaminergic D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone does not exhibit affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which relates to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central serotonergic and dopaminergic antagonism reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect on negative and affective symptoms of schizophrenia.

Pharmacokinetics. During metabolism, risperidone forms 9-hydroxyrisperidone, whose pharmacological activity is similar to that of the parent compound.

Absorption. After oral administration, risperidone is completely absorbed, with peak plasma concentrations reached within 1–2 hours; in elderly patients, peak concentrations occur within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). Food intake does not affect absorption of the drug; therefore, risperidone can be administered independently of food intake. Absolute bioavailability is 66% in rapid metabolizers and 82% in poor metabolizers.

Distribution. Risperidone rapidly distributes throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and acid α1-glycoprotein. Protein binding of risperidone in plasma is 90%, and for 9-hydroxyrisperidone it is 77%. Steady-state concentrations of risperidone are achieved within 1 day in most patients. Steady-state concentrations of 9-hydroxyrisperidone are reached within 4–5 days.

Biological transformation and elimination. Risperidone is metabolized via CYP2D6 to 9-hydroxyrisperidone, which has pharmacological activity similar to risperidone. Together, these two compounds form the active antipsychotic moiety. The cytochrome CYP2D6 is subject to genetic polymorphism. In rapid metabolizers of CYP2D6, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in poor metabolizers, the conversion is much slower. Although rapid metabolizers have lower risperidone concentrations and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic moiety) after single and multiple doses are similar in both rapid and poor metabolizers of cytochrome CYP2D6. Another metabolic pathway for risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Within one week after drug administration, 70% of the dose is excreted in urine and 14% in feces. The concentration of risperidone and 9-hydroxyrisperidone in urine equals 35–45% of the administered dose. The remainder consists of inactive metabolites. After oral administration in psychotic patients, the elimination half-life of risperidone is 3 hours. The elimination half-life of 9-hydroxyrisperidone and the active antipsychotic moiety is 24 hours, and in elderly patients, it is 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 impaired renal or hepatic function. Pharmacokinetic studies of single oral doses of risperidone in elderly patients showed, on average, 43% higher plasma concentrations of the active antipsychotic moiety, a 38% longer elimination half-life, and a 30% reduction in clearance of the active antipsychotic moiety. In adult patients with moderate renal impairment, clearance of the active antipsychotic moiety was ~48% of the clearance value in young healthy volunteers. In adult patients with severe renal impairment, clearance of the active antipsychotic moiety was ~31% of the clearance value in young healthy volunteers. The elimination half-life of the active moiety was 16.7 hours in adult patients, 24.9 hours in patients with moderate renal impairment (approximately 1.5 times longer than in adult patients), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in adult patients). Plasma risperidone concentrations were normal in patients with hepatic impairment, but the mean free fraction of risperidone in plasma was increased by 37.1%. Oral clearance and elimination half-life of risperidone and its active metabolites in adult patients with moderate or severe hepatic impairment did not differ significantly from those in healthy volunteers.

Children. The pharmacokinetics of risperidone, 9-hydroxyrisperidone, and the active antipsychotic moiety in children are similar to those in adults.

Sex, race, and smoking. Population pharmacokinetic analysis did not reveal any significant influence of sex, race, or smoking on the pharmacokinetics of risperidone and its active antipsychotic moiety.

Clinical characteristics.

Indications.

• Treatment of schizophrenia;
  • treatment of manic episodes of moderate to severe degree in bipolar disorders;
• short-term treatment (up to 6 weeks) of marked aggression in patients with moderate to severe Alzheimer's type dementia when there is a risk of harm to self or others and lack of response to non-pharmacological treatment methods (see sections "Method of administration and dosage" and "Special instructions");
• short-term symptomatic treatment (up to 6 weeks) of marked aggression in behavioral disorders in children from 5 years of age and adolescents with below-average intellectual development or intellectual disability diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological treatment should be an integral part of a comprehensive treatment program including psychological support and educational measures. It is recommended that risperidone be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or a physician experienced in treating behavioral disorders in children and adolescents.

Contraindications.

Hypersensitivity to the active ingredient or to any excipient of the medicinal product. Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances). Dementia and suspected dementia with Lewy bodies (in addition to dementia symptoms, at least two of the following symptoms: 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, caution is recommended when prescribing Risperidone-Teva together with medicinal products that prolong the QT interval, particularly antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, certain antimalarials (particularly quinine and mefloquine), and medicinal products that disturb electrolyte balance (causing hypokalemia, hypomagnesemia), cause bradycardia, as well as with medicinal products that inhibit hepatic metabolism of risperidone. The list provided is indicative and not exhaustive.

Central-acting medicinal products and alcohol. Due to an increased risk of sedative effects, risperidone should be used cautiously in combination with substances affecting the CNS, such as alcohol, opioids, antihistamines, and benzodiazepines.

Levodopa and dopamine agonists. Risperidone-Teva may have antagonistic effects to levodopa and other dopamine agonists. If such a combination is nevertheless necessary, especially in the terminal stage of Parkinson's disease, the minimum effective dose of each medicinal product should be prescribed.

Medicinal products with hypotensive effects. Post-marketing surveillance has revealed clinically significant arterial hypotension with concomitant use of risperidone and antihypertensive medicinal products.

Psychostimulants. Concomitant use of psychostimulants (particularly methylphenidate) with risperidone may lead to the emergence of extrapyramidal symptoms when changing the dosage of one or both medicinal products (see section "Special instructions").

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 excessive total active antipsychotic fraction effect.

Pharmacokinetic interactions

Food intake does not affect the absorption of risperidone.

Risperidone is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances altering CYP2D6 activity or strong inhibitors or inducers of CYP3A4 and/or P-gp activity may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.

Strong inhibitors of CYP2D6. Concomitant use of risperidone with a strong CYP2D6 inhibitor may increase plasma concentrations of risperidone, although the concentration of the active antipsychotic fraction is less significantly elevated. When using high doses of a strong CYP2D6 inhibitor, the concentration of the active antipsychotic fraction of risperidone may increase (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are also expected to similarly affect plasma concentrations of risperidone. At the initiation or discontinuation of concomitant use of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the risperidone dosage.

Inhibitors of CYP3A4 and/or P-gp. Concomitant use of risperidone with strong inhibitors of CYP3A4 and/or P-gp may significantly increase plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation or discontinuation of concomitant use of itraconazole or other strong inhibitors of CYP3A4 and/or P-gp, the physician should review the risperidone dosage.

Inducers of CYP3A4 and/or P-gp. Concomitant use of risperidone with strong inducers of CYP3A4 and/or P-gp may decrease plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation or discontinuation of treatment with carbamazepine or other strong inducers of CYP3A4 and/or P-gp, the physician should review the risperidone dosage. The effect of CYP3A4 inducers is time-dependent, with maximum effect achieved at least 2 weeks after initiation of treatment. Similarly, after discontinuation of treatment, CYP3A4 induction may persist for at least 2 weeks.

Medicinal products highly bound to plasma proteins. When risperidone is used concomitantly with medicinal products highly bound to plasma proteins, no clinically significant displacement of one medicinal product by another from plasma protein binding occurs. When multiple medicinal products are used concomitantly, the instructions for medical use of such products should be consulted regarding metabolic pathways and possible need for dose adjustment.

Children. Interaction studies have been conducted only in adult patients. It is unknown whether the obtained results can be applied to children.

Concomitant use of psychostimulants (particularly methylphenidate) with risperidone in children did not affect the pharmacokinetics and 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 and its active antipsychotic fraction. Rifampicin, a strong inducer of CYP3A4 and inducer of P-gp, reduces plasma concentrations of the active antipsychotic fraction.

Anticholinesterase agents. Donepezil and galantamine, substrates of CYP2D6 and CYP3A4, do not exhibit clinically significant effects on the pharmacokinetics of risperidone and the active antipsychotic fraction.

Antiepileptic agents. Carbamazepine, a strong inducer of CYP3A4 and inducer of 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 CYP3A4 and P-gp. Topiramate moderately reduces the bioavailability of risperidone and does not affect the bioavailability of the active antipsychotic fraction. Therefore, it is unlikely that this interaction may cause a clinically significant effect.

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

Antipsychotic medicinal products. Phenothiazines may increase plasma concentrations of risperidone, but do not affect the concentration of the active antipsychotic fraction.

Antiviral medicinal products. Protease inhibitors: data from studies are lacking; however, since ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and ritonavir-boosted protease inhibitors may increase the concentration of the active antipsychotic fraction of risperidone.

Beta-blockers. Some beta-blockers may increase plasma concentrations of risperidone without affecting the concentration 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.

Agents for gastrointestinal tract treatment. H2-receptor antagonists: cimetidine and ranitidine, weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone with a slight increase in bioavailability of the active antipsychotic fraction.

SSRIs and tricyclic antidepressants. Fluoxetine, a strong inhibitor of CYP2D6, increases plasma concentrations of risperidone and slightly increases the concentration of the active antipsychotic fraction. Paroxetine, a strong inhibitor of CYP2D6, increases plasma concentrations of risperidone, but at doses up to 20 mg/day less than the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may cause an increase in the concentration of the active antipsychotic fraction of risperidone. Tricyclic antidepressants may increase plasma concentrations of risperidone but do not affect the concentration 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 the concentration of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine above 100 mg/day may lead to an increase in the concentration 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 medicinal products. Aripiprazole, a substrate of CYP2D6 and CYP3A4: risperidone in tablet or injectable form does not affect the total 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. See section "Special instructions" regarding increased mortality in elderly patients with dementia who are concurrently receiving furosemide.

Special precautions for use.

Geriatric patients with dementia

Increased mortality. A meta-analysis of 17 controlled clinical trials of atypical antipsychotics (including risperidone) revealed a higher mortality rate in elderly patients with dementia treated with atypical antipsychotics compared to placebo. Placebo-controlled trials of risperidone in this patient group showed a mortality rate of 4.0% in the risperidone group compared to 3.1% in the placebo group. The odds ratio (95% confidence interval) was 1.21 (0.7; 2.1). The mean age of patients who died was 86 years (range: 67–100 years). Data from two large observational studies indicate that elderly patients with dementia treated with conventional antipsychotics also have a slightly increased risk of fatal outcomes compared to patients not receiving antipsychotics. Data are insufficient to precisely estimate the magnitude of risk, and the reason for the increased risk is unknown.

Concomitant use with furosemide. In placebo-controlled trials of risperidone among elderly patients with dementia, an increased mortality rate was observed when furosemide was used concomitantly with risperidone (7.3%; mean age 89 years, range 75–97 years), compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70–96 years) or furosemide alone (4.1%; mean age 80 years, range 67–90 years). Increased mortality with the combination of furosemide and risperidone was observed in two out of four clinical trials. No increased mortality was observed in patients taking risperidone concomitantly with other diuretics. The pathophysiological mechanisms of these changes have not been identified, and the cause of death was not uniform. However, particular caution should be exercised when prescribing this combination after careful evaluation of the potential risks and therapeutic benefits, or when co-administering with other potent diuretics. Among patients taking risperidone with other diuretics, the risk of fatal outcome did not increase. Dehydration, regardless of treatment, is a general risk factor for fatal outcome and requires careful prevention in elderly patients with dementia.

Cerebrovascular adverse reactions (CVAE). In placebo-controlled clinical trials, elderly patients with dementia receiving risperidone experienced approximately three times higher rates 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, primarily involving elderly patients with dementia (aged 65 years and older), showed cerebrovascular adverse events (serious and non-serious combined) in 3.3% (33/1009) of patients treated with risperidone compared to 1.2% (8/712) of those on placebo. The ratio 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 of CVAE cannot be excluded when treating 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 is significantly higher in patients with mixed or vascular dementia compared to Alzheimer's dementia. Therefore, risperidone is not recommended for patients with dementia other than Alzheimer's type.

The risk and therapeutic benefits of using risperidone in elderly patients with dementia should be evaluated, considering prognostic factors for stroke risk. Patients and caregivers should be informed about the need to promptly report symptoms and signs of potential cerebrovascular disorders, including sudden weakness or numbness of the face, arms, or legs, speech or vision disturbances. In such cases, all therapeutic options should be urgently considered, including discontinuation of risperidone.

For persistent aggression in patients with moderate to severe Alzheimer's dementia, Risperidone-Teva should be prescribed only for short-term use as an adjunct to non-pharmacological interventions when these are ineffective or limited and there is a threat of harm to self or others. Regular assessment of the patient's condition and justification for continued treatment are required.

Orthostatic hypotension. Orthostatic hypotension (especially at the beginning of treatment) may occur due to the α1-blocking effect of risperidone. Clinically significant hypotension has been reported in the post-marketing period with concomitant use of risperidone and antihypertensive agents. Risperidone-Teva should be used with caution in patients with known cardiovascular disorders (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease). In such cases, the dose should be gradually adjusted (see section "Dosage and administration"). Consideration should be given to reducing the dose if arterial hypotension occurs.

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

Patients with clinically significant neutropenia should be closely monitored for fever or signs of infection, and appropriate treatment should be initiated immediately if such symptoms occur. In patients with severe neutropenia (<1×10⁹/L), risperidone therapy should be discontinued and leukocyte counts monitored until they return to normal.

Tardive dyskinesia/extrapyramidal symptoms. Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly of the tongue and/or face), has been observed with drugs possessing dopamine receptor antagonist properties. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs or symptoms of tardive dyskinesia appear, discontinuation of all antipsychotics should be considered. Caution is advised when co-administering psychostimulants (e.g., methylphenidate) with risperidone, as extrapyramidal symptoms may occur when adjusting the dose of one or both agents (see section "Interaction with other medicinal products and other forms of interaction"). Gradual discontinuation of psychostimulants is recommended.

Malignant neuroleptic syndrome. Rare cases of malignant neuroleptic syndrome have been reported with classical neuroleptics, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated creatine phosphokinase levels. Other manifestations 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, the physician should evaluate the risk-benefit ratio. Treatment may worsen the course of Parkinson's disease. Patients with either of these conditions may have an increased risk of developing neuroleptic malignant syndrome and increased sensitivity to antipsychotics (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, prior excessive body weight, which could be a triggering factor, was reported. Very rarely, ketoacidosis and rarely diabetic coma have been reported. Therefore, appropriate clinical monitoring according to standards for antipsychotic use is recommended. Patients taking any atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should undergo regular evaluation for worsening glucose control.

Weight gain. Significant weight gain has been reported with risperidone use. Body weight should be monitored.

Hyperprolactinemia. Hyperprolactinemia is a common adverse reaction during treatment with risperidone. In patients with signs of prolactin-related adverse reactions (gynecomastia, menstrual disorders, anovulation, fertility impairment, decreased libido, erectile dysfunction, galactorrhea), monitoring of plasma prolactin levels is recommended. Tissue culture studies suggest that prolactin may stimulate growth of human breast tumor cells. Although clinical and epidemiological studies have not established a clear link with antipsychotic use, risperidone should be prescribed with caution in patients with relevant medical history. Risperidone-Teva should be used with caution in patients with hyperprolactinemia or in whom prolactin-dependent tumors are not excluded.

QT interval prolongation. Cases of QT interval prolongation have been reported very rarely in the post-marketing period. As with any other antipsychotics, caution is required when prescribing risperidone to patients with known cardiovascular disorders, family history of QT prolongation, bradycardia, or electrolyte imbalances (hypokalemia, hypomagnesemia), as such treatment may increase the risk of arrhythmogenic effects. Caution is also advised when prescribing combinations of drugs capable of prolonging the QT interval.

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

Priapism. Due to α-adrenergic blocking effects, treatment with Risperidone-Teva may be associated with priapism.

Body temperature regulation. Antipsychotics are associated with impaired ability of the body to regulate core body temperature. Appropriate caution is recommended when prescribing risperidone to patients exposed to conditions that may increase core body temperature, such as intense physical exertion, exposure to high environmental temperatures, concomitant treatment with anticholinergic agents, or dehydration.

Antiemetic effect. An antiemetic effect of risperidone has been reported. This property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, or brain tumors.

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

Venous thromboembolism. Cases of venous thromboembolism have been reported during treatment with antipsychotics. Since patients requiring antipsychotic treatment often have acquired risk factors for venous thromboembolism, all risk factors should be identified before and during treatment with Risperidone-Teva, 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. IFIS increases the risk of ocular complications during and after surgery. The ophthalmic surgeon should be informed about past or current use of antipsychotics. The potential benefit of discontinuing α1-adrenergic blockers before surgery has not been established; the risk of discontinuing antipsychotic treatment should be weighed.

Children. Before prescribing Risperidone-Teva to children or adolescents with behavioral disorders, the risk-benefit ratio should be carefully considered, and physical and social causes of aggressive behavior, such as pain stimuli or inappropriate response to the environment, should be evaluated. The sedative effect of risperidone should be carefully monitored in pediatric patients due to possible effects on learning ability. Adjusting the timing of risperidone administration may improve the impact of sedation on children's and adolescents' attention. Risperidone treatment has been associated with moderate increases in body weight and body mass index (BMI). Weight should be measured before starting treatment and monitored regularly thereafter. Growth changes observed in long-term open-label extension studies remained within expected age norms. The effect of long-term risperidone treatment on sexual development and growth has not been adequately studied. Due to the potential impact of prolonged hyperprolactinemia on physical and sexual development in children and adolescents, regular clinical assessments of endocrine status are required, including data on height, weight, evaluation of sexual development, monitoring of menstrual cycles, and other potential prolactin-related effects.

Results from a small post-marketing observational study demonstrated that patients aged 8–16 years taking risperidone were on average 3.0–4.8 cm taller compared to patients taking other antipsychotics. These data are insufficient to determine whether risperidone affects final adult height or whether the results were due to a direct effect of risperidone on bone growth, the underlying disease, or improved control of the underlying condition leading to increased linear growth.

Regular monitoring for extrapyramidal symptoms and other movement disorders is required during risperidone treatment. Dosage recommendations for children are provided in the section "Dosage and administration."

Use during pregnancy or breastfeeding.

Pregnancy. Controlled studies in pregnant women have not been conducted. Animal studies did not reveal teratogenic effects of risperidone, but other forms of reproductive toxicity were observed. The potential risk to humans is unknown. Newborns whose mothers took 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, hypertonia, hypotonia, tremor, somnolence, respiratory disturbances, or feeding difficulties. These complications may vary in severity and duration. Therefore, newborns should be carefully monitored. Risperidone is not recommended during pregnancy except in cases of life necessity. If discontinuation of the drug during pregnancy is necessary, it should not be done abruptly.

Breastfeeding. In animal studies, risperidone and 9-hydroxyrisperidone were excreted in milk. Risperidone and 9-hydroxyrisperidone pass into 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 weighed.

Fertility. Like other dopamine D2 receptor antagonists, risperidone increases prolactin levels. Hyperprolactinemia may suppress gonadotropin-releasing hormone production in the hypothalamus and lead to decreased pituitary gonadotropin secretion. This may inhibit reproductive function by disrupting gonadal steroidogenesis in both women and men. No such effects were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product Risperidone-Teva may have a slight or moderate effect on the ability to drive and operate complex machinery due to its potential effects on the nervous system and vision. During treatment, patients should refrain from driving or operating machinery until individual sensitivity to the drug is known.

Method of Administration and Dosage

Dosage

Schizophrenia

Adults

Risperidone-Teva may be administered once or twice daily.

Treatment should be initiated at a dose of 2 mg of Risperidone-Teva per day; on the second day, the dose may be increased to 4 mg. Thereafter, the dose may be maintained unchanged or, if necessary, further individual dose adjustments may be made. The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or a lower initial and maintenance dose.

Doses exceeding 10 mg/day have not demonstrated greater efficacy compared to lower doses but may increase the risk of extrapyramidal symptoms. The safety of doses above 16 mg/day has not been studied, and doses exceeding this level are not recommended.

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 by increments of 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-Teva is 2 mg once daily. The dose may be individually increased by increments of 1 mg/day no more frequently than every 24 hours. The recommended dose range is 1 to 6 mg per day. The use of risperidone at doses exceeding 6 mg/day in patients with manic episodes has not been studied.

As with other forms of symptomatic treatment, long-term use of Risperidone-Teva should be periodically reviewed and adjusted throughout the course of therapy.

Elderly patients (aged 65 years and older)

The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily by increments of 0.5 mg twice daily. Due to limited experience with use in elderly patients, caution is recommended.

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, the dose may be increased to 1 mg twice daily to achieve an effective response.

Risperidone 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, long-term use of Risperidone-Teva should be periodically reviewed and adjusted throughout the course of therapy.

Short-term symptomatic treatment (up to 6 weeks) of marked aggression in behavioral disorders

Children and adolescents aged 5 to 18 years

Patients with body weight ≥ 50 kg

The recommended initial dose is 0.5 mg once daily. If necessary, the dose may be adjusted by increments of 0.5 mg once daily no more frequently than every other day. The optimal dose for most patients is 1 mg once daily. However, some patients may achieve a positive effect with no more than 0.5 mg once daily, while others may require 1.5 mg once daily.

Patients with body weight < 50 kg

The recommended initial dose is 0.25 mg once daily. If necessary, the dose may be adjusted by increments of 0.25 mg once daily no more frequently than every other day. The optimal dose for most patients is 0.5 mg once daily. However, some patients may require no more than 0.25 mg once daily to achieve a positive effect, while others may require 0.75 mg once daily.

As with other forms of symptomatic treatment, long-term use of Risperidone-Teva should be periodically reviewed and adjusted throughout the course of therapy.

Children

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

Patients with hepatic or 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, plasma concentrations of free risperidone are increased.

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

Risperidone-Teva should be used with caution in these patient groups.

Switching from other antipsychotic medications. If clinically justified, a gradual transition from previous antipsychotic therapy to Risperidone-Teva is recommended. When switching from depot antipsychotic formulations, treatment with Risperidone-Teva should be initiated instead of the next scheduled injection. The need for continued use of antiparkinsonian medications should be periodically evaluated.

Method of administration. Risperidone-Teva is intended for oral use. The solution is supplied with a dosing device. Only the dosing device provided with this medicinal product should be used to measure the prescribed dose. Measure the exact amount of medication required. Note: for a small dose, e.g., 0.25 mg, measure 0.25 mL (a quarter of a milliliter); for a 0.5 mg dose, measure 0.5 mL (half a milliliter).

Food does not affect the absorption of risperidone. When discontinuing treatment, gradual dose reduction is recommended. Isolated cases of acute withdrawal symptoms after abrupt discontinuation of high-dose antipsychotics have been reported, including nausea, vomiting, excessive sweating, and insomnia. Psychotic symptoms may also recur, and uncontrolled movements (e.g., akathisia, dystonia, and dyskinesia) have been reported.

Method of administration

Fig. 1

The bottle has a child-resistant cap. To open, press the plastic cap down firmly and turn counterclockwise.

Fig. 2

Insert the dosing device into the bottle through the opening in the adapter (which holds the doser during filling).

While holding the lower rim of the dosing device, pull the plunger to the required mark in milliliters or milligrams.

Fig. 3

While holding the lower rim, remove the dosing device from the bottle.

Empty the contents of the dosing device into any non-alcoholic beverage (except tea) by pressing the plunger.

Close the bottle, rinse the doser with water, and allow it to air dry.

Fig. 4

The cardboard box also contains an adapter for the dosing device, which can be used for its storage. On the concave side of the adapter, there is an adhesive surface that can be attached to the bottle. Remove the protective foil from the adhesive surface.

Fig. 5

Press the adhesive surface of the adapter (with the large opening facing upwards) onto the lower part of the bottle. The cleaned dosing device can now be inserted into the adapter.

Children.

Risperidone is used to treat marked aggression in behavioral disorders in children aged 5 years and older.

Overdose.

Symptoms. Signs and symptoms reported in overdose cases are generally consistent with an exaggeration of the known pharmacological effects of risperidone. These include somnolence and sedation, tachycardia, hypotension, and extrapyramidal symptoms. QT interval prolongation and seizures have also been reported in overdose cases. Ventricular fibrillation/torsades de pointes has been reported in combined overdose with risperidone and paroxetine. In cases of acute overdose, the possibility of multiple drug ingestion should be considered.

Treatment. To ensure adequate oxygenation and ventilation, the airway should be cleared and maintained. If the drug was ingested within the past hour, activated charcoal with a laxative should be considered. Continuous cardiovascular monitoring, including continuous ECG monitoring to detect possible arrhythmias, should be initiated immediately. Risperidone has no specific antidote; therefore, appropriate supportive measures should be applied. In cases of acute overdose, potential drug interactions involving multiple agents should be evaluated. Hypotension or vascular collapse should be treated with appropriate measures, including intravenous fluids and/or sympathomimetic agents. Anticholinergic agents should be administered in cases of acute extrapyramidal symptoms. Continuous medical monitoring should be maintained until full recovery of the patient.

Adverse Reactions

The most commonly reported adverse reactions (frequency ≥ 10%) include parkinsonism, sedative effect/somnolence, headache, and insomnia. Dose-dependent adverse reactions include parkinsonism and akathisia. The adverse reactions listed below are 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 (frequency cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.

Infections and infestations.
Common: pneumonia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, ear infections, influenza.
Uncommon: respiratory tract infections, cystitis, eye infections, tonsillitis, onychomycosis, cellulitis, localized infection, viral infections, acrodermatitis.
Rare: infection.

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 reaction^c.

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

Metabolism and nutrition disorders.
Common: weight increased, increased appetite, decreased appetite.
Uncommon: diabetes mellitus^b, hyperglycaemia, polydipsia, weight decreased, 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, nervousness, nightmares.
Rare: catatonia, somnambulism, sleep-related eating disorder, 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, unresponsiveness, loss of consciousness, depressed level of consciousness, seizures^d, syncope, psychomotor hyperactivity, gait instability, incoordination, postural dizziness, attention disturbance, dysarthria, dysgeusia, hypoesthesia, paraesthesia.
Rare: neuroleptic malignant syndrome, cerebrovascular disorder, diabetic coma, head bobbing.

Eye disorders.
Common: blurred vision, conjunctivitis.
Uncommon: photophobia, dry eyes, increased lacrimation, eye hyperaemia.
Rare: glaucoma, eye movement disorders, rotary nystagmus, 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 electrocardiogram, bradycardia, ECG abnormalities, palpitations.
Rare: sinus arrhythmia.
Not known: postural orthostatic tachycardia syndrome.

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

Respiratory, thoracic and mediastinal disorders.
Common: dyspnoea, throat and larynx pain, cough, epistaxis, nasal congestion.
Uncommon: aspiration pneumonia, pulmonary congestion, worsening of airway patency, wheezing, stridor, dysphonia, respiratory distress.
Rare: sleep apnoea syndrome, hyperventilation.

Gastrointestinal disorders.
Common: abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhoea, dyspepsia, dry mouth, toothache.
Uncommon: faecal incontinence, faecal impaction, gastroenteritis, dysphagia, flatulence.
Rare: pancreatitis, gastrointestinal obstruction, tongue swelling, cheilitis.
Very rare: intestinal obstruction.

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 disorder, skin injury.
Rare: drug eruption, dandruff.
Very rare: angioedema.
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: pollakiuria, urinary retention, dysuria.

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

Reproductive system and breast disorders.
Uncommon: erectile dysfunction, ejaculation disorder, amenorrhoea, menstrual disorder^d, gynaecomastia, galactorrhoea, sexual dysfunction, breast pain, breast discomfort, vaginal discharge.
Rare: priapism^c, menstrual delay, breast engorgement, 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, pyrexia, unusual feelings, discomfort.
Rare: hypothermia, decreased body temperature, cold extremities, drug withdrawal syndrome, induration^c.

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

a In certain cases, hyperprolactinaemia may lead to gynaecomastia, menstrual disorders, amenorrhoea, galactorrhoea, anovulation, fertility disorders, erectile dysfunction, and decreased libido.

b During placebo-controlled studies, diabetes mellitus was reported in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients taking risperidone.

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

d Possible extrapyramidal disorders: parkinsonism (hypersalivation, muscle and joint stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, mask-like face, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, myoclonus), dystonia. Dystonia may present as dystonia, hypertonia, torticollis, involuntary muscle contractions, myogenic contracture, blepharospasm, eye movements, tongue paralysis, facial tics, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus.

An extended list of symptoms is included, not all of which necessarily have an extrapyramidal origin. Insomnia includes: difficulty falling asleep, intrasomniac disturbance. Seizures include: grand mal epileptic seizure. Menstrual disorders include: irregular menstruation, oligomenorrhoea. Oedema includes: generalized oedema, peripheral oedema, pitting oedema.

Adverse reactions of paliperidone. Paliperidone is the active metabolite of risperidone; therefore, the safety profiles of these drugs (both oral and injectable forms) are similar. In addition to the adverse reactions listed above, post-marketing reports with paliperidone include postural orthostatic tachycardia syndrome, which may also occur with risperidone.

Adverse reactions typical of antipsychotic medicinal products. As with other antipsychotics, very rare cases of QT interval prolongation have been reported post-marketing with risperidone. Other cardiac adverse reactions associated with QT-prolonging antipsychotics include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and flutter/fibrillation.

Venous thromboembolism. Venous thromboembolic events, including pulmonary embolism and deep vein thrombosis, have been reported with antipsychotic agents.

Weight gain. In placebo-controlled studies of 6 to 8 weeks duration, a statistically significant difference in the incidence of ≥7% body weight gain was observed in patients treated with risperidone (18%) compared to placebo (9%).

In 3-week placebo-controlled studies in adult patients with acute mania, the incidence of ≥7% weight gain was similar between risperidone (2.5%) and placebo (2.4%), and slightly higher in the active control group (3.5%). In paediatric patients with behavioural disorders, mean body weight increased by 7.3 kg after 12 months of treatment. Expected annual weight gain in children aged 5–12 years with normal body weight is 3–5 kg. From age 12, girls continue to gain 3–5 kg per year, while boys gain an average of 5 kg per year.

Additional information on specific patient populations. The following adverse reactions were reported more frequently in elderly patients with dementia and in children compared to adults.

Elderly patients with dementia. In elderly patients with dementia, transient ischaemic attack and stroke were reported during clinical trials at frequencies of 1.4% and 1.5%, respectively. Additionally, the following adverse reactions were reported with a frequency ≥5% and at least twice as high compared to other adult patient groups: urinary tract infections, peripheral oedema, somnolence, 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 5–17 years) with a frequency ≥5% and at least twice as high compared to adults: somnolence/sedative effect, 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 is not fully understood.

Shelf life. 5 years. After first opening – 6 months.

Storage conditions.

The medicinal product does not require special storage conditions. Do not freeze.

Keep out of the reach and sight of children.

Packaging.

30 or 100 ml of solution in a bottle; 1 bottle with adapter and dosing device in a carton.

Prescription status. Prescription only.

Manufacturer. Merckle GmbH.

Manufacturer’s address and location of operations.

Ludwig-Merckle-Strasse 3, 89143 Blaubeuren, Germany.