Rosemid® odt
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSEMIDE® ODT (ROSEMIDE® ODT)
Composition:
Active substance: risperidone;
each tablet contains 1 mg or 2 mg or 4 mg of risperidone;
Excipients: mannitol (E 421), sodium croscarmellose, iron oxide red (E 172), aspartame (E 951), flavouring agent "Powder 599399TP0951", flavouring agent Powdarome "Mint Premium", calcium stearate.
Pharmaceutical form. Orodispersible tablets.
Main physicochemical properties:
1 mg and 2 mg tablets: round, bevel-edged tablets, pink in colour, with speckles, embossed with « » on one side and smooth on the other;
4 mg tablets: round, biconvex tablets, pink in colour, with speckles, smooth on both sides.
Pharmacotherapeutic group. Antipsychotic agents. ATC code N05AX08.
Pharmacological properties.
Pharmacodynamics.
Risperidone is a selective monoaminergic antagonist with unique properties. It exhibits high affinity for serotonin 5-HT2 and dopamine D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone does not exhibit affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against productive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.
Pharmacokinetics.
Orally disintegrating tablets of risperidone and oral solution are bioequivalent to film-coated tablets.
Risperidone is metabolized to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to that of risperidone.
Absorption.
After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1–2 hours; in elderly patients, peak concentrations are reached within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV=25%). Relative bioavailability after oral administration of risperidone in tablet form is 94% (CV=10%) compared to the solution form. Food does not affect drug absorption; therefore, risperidone can be administered independently of food intake. Absolute bioavailability is 66% in rapid metabolizers and 82% in slow metabolizers.
Distribution.
Risperidone is rapidly distributed throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and acid α1-glycoprotein. Risperidone is 90% protein-bound in plasma, while 9-hydroxyrisperidone is 77% protein-bound. Steady-state concentrations of risperidone in the body are achieved within 1 day in most patients. Steady-state concentrations of 9-hydroxyrisperidone are reached within 4–5 days.
Biological transformation and elimination.
Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. Cytochrome CYP2D6 is subject to genetic polymorphism. In rapid metabolizers, risperidone is quickly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, this conversion occurs much more slowly. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in rapid metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both rapid and slow metabolizers of cytochrome CYP2D6.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Approximately 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 accounts for 35–45% of the administered dose. The remainder consists of inactive metabolites. After oral administration in patients with psychosis, the elimination half-life is approximately 3 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, 34 hours.
Linearity.
Plasma concentrations of risperidone are proportional to the drug dose (within the therapeutic dose range).
Elderly patients and patients with renal or hepatic impairment.
A pharmacokinetic study of single-dose administration in elderly patients demonstrated that these patients have a 43% higher concentration of the active antipsychotic fraction, a 38% longer elimination half-life, and a 30% lower clearance of the active antipsychotic fraction.
In adult patients with impaired renal function, clearance values of the active fraction were ~48% of those in adults without renal impairment. In adult patients with severe renal impairment, clearance values were ~31% of those in adults without renal impairment. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (approximately 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in young adults). In patients with hepatic insufficiency, normal plasma concentrations of risperidone were observed, but the mean value of the free fraction of risperidone in plasma was increased by 37.1%.
After oral administration, clearance and elimination half-life values of risperidone and the active antipsychotic fraction in patients with moderate to severe hepatic impairment did not differ significantly from those in young healthy volunteers.
Children.
The pharmacokinetics of risperidone, 9-hydroxyrisperidone, and the active antipsychotic fraction in children are similar to those in adults.
Sex, race, and smoking.
Population pharmacokinetic analysis did not reveal any significant influence of sex, age, or smoking habit on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Clinical characteristics.
Indications.
- Treatment of schizophrenia and other psychiatric disorders, including maintenance therapy, in patients who have responded to treatment, with the aim of preventing disease relapse;
- short-term treatment (up to 12 weeks) of marked aggression or severe psychiatric symptoms in patients with Alzheimer's type dementia when there is a threat of harm to self or others and in the absence of response to non-pharmacological treatment methods (see sections "Dosage and administration" and "Special precautions");
- temporary treatment of manic episodes in bipolar disorders (adjunctive therapy in combination with mood stabilizers as initial treatment or as monotherapy for a duration of up to 12 weeks). For patients who do not respond to treatment, alternative treatment options should be considered, including discontinuation of risperidone.
Treatment may be continued for up to 12 weeks when risperidone is not used in combination with mood stabilizers. Such prolonged treatment should be applied with the aim of consolidating the patient's response. When risperidone is used in combination with mood stabilizers, treatment may be discontinued earlier, as the therapeutic effect of mood stabilizers in combination with risperidone becomes evident within the first few weeks of treatment.
No studies have been conducted regarding relapse prevention.
Due to the specific course of the disease and medications used for treatment, including risperidone, attention should be paid to the emergence of depressive symptoms following the initial response to treatment.
- Symptomatic treatment of defiant oppositional disorders or other social behavior disorders in children, adolescents, and adults with below-average intellectual development or intellectual disability who exhibit destructive behaviors (impulsivity, self-aggression);
- symptomatic treatment of autistic disorders in children aged 5 years and older, in whom symptoms range from hyperactivity to irritability (including aggression, self-injurious behavior, anxiety, and pathological repetitive behaviors). Treatment should be initiated and conducted under the supervision of an experienced physician. The use of medications should be part of an integrated treatment approach, including social and psychotherapeutic treatment methods.
Contraindications.
Hypersensitivity to the active ingredient or to any of the excipients of the medicinal product.
Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances).
Dementia and suspected dementia with Lewy bodies (in addition to dementia symptoms, at least two of the following: parkinsonism, visual hallucinations, gait instability).
Interaction with other medicinal products and other types of interactions.
Pharmacodynamic interactions.
Medicinal products that prolong the QT interval.
As with other antipsychotics, caution should be exercised when prescribing risperidone with medicinal products that prolong the QT interval, such as antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, certain antimalarials (quinine, mefloquine), and products causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or agents that inhibit hepatic metabolism of risperidone. This list is indicative and not exhaustive.
Central-acting agents and alcohol.
Risperidone should be used cautiously in combination with other centrally acting substances, including alcohol, opioids, antihistamines, and benzodiazepines, due to an increased risk of sedation.
Levodopa and dopamine agonists.
Risperidone may exhibit antagonistic effects to levodopa and other dopamine agonists. If such a combination is considered necessary, especially in the terminal stage of Parkinson's disease, the lowest effective doses of each drug should be prescribed.
Medicinal products with hypotensive effects.
During the post-marketing period, cases of clinically significant hypotension have been observed with concomitant use of risperidone and antihypertensive medicinal products.
Psychostimulants.
The use of risperidone in combination with psychostimulants (e.g., methylphenidate) may lead to the emergence of extrapyramidal symptoms after dose adjustment of one or both agents (see section "Special precautions").
Paliperidone.
Concomitant use of oral risperidone with paliperidone is not recommended, as paliperidone is an active metabolite of risperidone and their combination may lead to an additive effect of the active antipsychotic fraction.
Pharmacokinetic interactions.
Food does not affect the absorption of risperidone.
Risperidone is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or potent inhibitors or inducers of CYP3A4 and/or P-gp activity, may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.
Potent CYP2D6 inhibitors.
Concomitant use of risperidone with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but less so than the concentration of the active antipsychotic fraction. Higher doses of a potent CYP2D6 inhibitor may increase the concentration of the active antipsychotic fraction of risperidone (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are expected to affect plasma concentrations of risperidone similarly. At the start of concomitant use, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the risperidone dose.
Inhibitors of CYP3A4 and P-gp.
Concomitant use of risperidone with potent inhibitors of CYP3A4 and/or P-gp may significantly increase plasma concentrations of the active antipsychotic fraction of risperidone. At the start of concomitant use, and upon discontinuation of itraconazole or other potent inhibitors of CYP3A4 and/or P-glycoprotein, the physician should review the risperidone dose.
Inducers of CYP3A4 and P-gp.
Concomitant use of risperidone with potent inducers of CYP3A4 and/or P-gp may reduce plasma concentrations of the active antipsychotic fraction of risperidone. At the start of therapy, and upon discontinuation of carbamazepine or other strong inducers of CYP3A4/P-glycoprotein, the physician should review the risperidone dose. The effect of CYP3A4 inducers depends on time, with maximum impact achieved at least 2 weeks after initiation of treatment. Accordingly, after discontinuation, induction of CYP3A4 may persist for at least 2 weeks.
Medicinal products with high plasma protein binding.
When risperidone is used concomitantly with other medicinal products that are highly bound to plasma proteins, clinically significant displacement of either agent from the protein fraction has not been observed. When used concomitantly with such a medicinal product, the prescribing information should be consulted regarding metabolic pathways and the need for dose adjustment.
Children.
Interaction studies have been conducted only in adult patients. It is unknown whether the results obtained can be applied to children.
Concomitant use of psychostimulants (e.g., methylphenidate) with risperidone in children did not affect the pharmacokinetics or efficacy of risperidone.
Effect of other medicinal products on the pharmacokinetics of risperidone.
Antibacterial medicinal products
- Erythromycin, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Rifampicin, a potent inducer of CYP3A4 and an inducer of P-gp, reduces plasma concentrations of the active antipsychotic fraction.
Cholinesterase inhibitors
- Donepezil and galantamine, substrates of CYP2D6 and CYP3A4, do not demonstrate clinically significant effects on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Antiepileptic medicinal products
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Carbamazepine, a potent inducer of CYP3A4 and an inducer of P-gp, has demonstrated an effect in reducing plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may be observed with phenytoin and phenobarbital, which are also inducers of hepatic enzymes CYP3A4 and P-glycoprotein.
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Topiramate moderately reduces the bioavailability of risperidone and does not affect the bioavailability of the active antipsychotic fraction. It is unlikely that this interaction may cause a clinically significant effect.
Antifungal medicinal products
- Itraconazole, a potent inhibitor of CYP3A4 and an inhibitor of P-gp, at a dose of 200 mg per day, increases plasma concentrations of the active antipsychotic fraction by approximately 70% when used concomitantly with risperidone at doses of 2 to 8 mg per day.
- Ketoconazole, a potent inhibitor of CYP3A4 and an inhibitor of P-gp, at a dose of 200 mg per day, increases plasma concentrations of risperidone and decreases plasma concentrations of 9-hydroxyrisperidone.
Antipsychotic medicinal products
- Phenothiazines may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction.
Antiviral medicinal products
- Protease inhibitors: data from studies are lacking; since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and protease inhibitors boosted with ritonavir may increase plasma concentrations of the active antipsychotic fraction of risperidone.
Beta-blockers
- Some beta-blockers may increase plasma concentrations of risperidone, but do not affect plasma concentrations of the active antipsychotic fraction.
Calcium channel blockers
- Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases plasma concentrations of risperidone and the active antipsychotic fraction.
Medicinal products for gastrointestinal disorders
- H2-receptor antagonists: cimetidine and ranitidine, weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone and minimally affect the bioavailability of the active antipsychotic fraction.
SSRIs and tricyclic antidepressants
- Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but 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 per day) less so than the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction.
- Tricyclic antidepressants may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at doses up to 100 mg per day, do not cause clinically significant changes in the concentration of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg per day may increase the concentration of the active antipsychotic fraction of risperidone.
Effect of risperidone on the pharmacokinetics of other medicinal products.
Antiepileptic medicinal products
- Risperidone has no clinically significant effect on the pharmacokinetics of valproate or topiramate.
Antipsychotic medicinal products
- Aripiprazole, a substrate of CYP2D6 and CYP3A4: oral or injectable formulations of risperidone do not affect the pharmacokinetics of aripiprazole or its active metabolite dehydroaripiprazole.
Cardiac glycosides
- Risperidone has no clinically significant effect on the pharmacokinetics of digoxin.
Lithium
- Risperidone has no clinically significant effect on the pharmacokinetics of lithium.
Concomitant use of risperidone with furosemide.
See section "Special precautions" regarding increased mortality in elderly patients with dementia when used concomitantly with furosemide.
Special precautions for use.
Geriatric patients with dementia.
Increased mortality.
An increased mortality rate has been observed in elderly patients with dementia treated with atypical antipsychotic agents compared to placebo-treated patients in a meta-analysis of 17 controlled trials of atypical antipsychotics, including risperidone. In a placebo-controlled trial using risperidone in this patient population, the incidence of deaths was 4.0% compared to 3.1% in the placebo group. The mean age of patients who died was 86 years (range: 67–100 years). A specific profile of risk factors for mortality in patients receiving risperidone has not been identified. Causes of death were typical for this age group (≥65 years) and included cardiovascular and cerebrovascular diseases, malignancies, infections (e.g., pneumonia), and diabetes mellitus.
Concomitant use with furosemide.
In a placebo-controlled trial in elderly patients with dementia, an increased mortality rate was observed when risperidone was used concomitantly with furosemide (7.3%; mean age: 89 years, range: 75–97 years), compared to patients treated with risperidone alone (3.1%; mean age: 84 years, range: 70–96 years) or furosemide alone (4.1%; mean age: 80 years, range: 67–90 years). Increased mortality in patients treated with risperidone and furosemide together was observed in two out of four clinical trials. No increased mortality was observed in patients who received risperidone concomitantly with other diuretics.
The pathophysiological mechanisms underlying this observation have not been established. The cause of death was also not uniform. However, particular caution should be exercised when prescribing the drug in such cases, and a risk-benefit assessment of this combination or combination with other potential diuretics should be performed before prescribing. Regardless of treatment, dehydration was a common risk factor for mortality and should be carefully monitored in patients with dementia.
Cerebrovascular adverse reactions.
In placebo-controlled clinical trials in patients with dementia treated with risperidone, a higher incidence of cerebrovascular adverse events (strokes and transient ischemic attacks), including fatal outcomes, was observed compared to placebo (mean age: 85 years; range: 73–97 years).
Pooled data from six placebo-controlled trials involving elderly patients with dementia (aged ≥65 years) showed cerebrovascular disorders (including severe cases) occurred in 3.3% (33/989) of patients treated with risperidone compared to 1.2% (8/693) of patients receiving placebo. The odds ratio (95% CI) between the risperidone and placebo groups was 2.96 (1.33; 7.45), and in the subgroup of patients with vascular dementia, it was 5.26 (1.18; 48.11).
The risk of cerebrovascular adverse effects is significantly higher in patients with mixed or vascular dementia compared to Alzheimer’s dementia. Therefore, risperidone should not be prescribed to patients with types of dementia other than Alzheimer’s dementia.
All risks and benefits of prescribing risperidone to elderly patients with dementia, particularly the risk of stroke, should be carefully weighed. Risperidone should be prescribed with particular caution to patients with dementia who have hypertension, cardiovascular disease, or vascular dementia. Patients and caregivers should be instructed to immediately report signs of possible cerebrovascular events, such as sudden weakness, facial, arm, or leg numbness, speech disturbances, or visual disturbances. All possible treatment options, including discontinuation of risperidone therapy, should be promptly considered.
Children.
Before prescribing risperidone to children, the risk-benefit ratio should be carefully evaluated. The need for continued treatment should be regularly and thoroughly assessed. The indications “symptomatic treatment of social behavior disorders, oppositional defiant disorders and/or other social behavior disorders” and “autistic disorders” have been studied only in children aged 5 years and older. Therefore, risperidone should not be prescribed for these indications in children under 5 years of age.
There is no experience with the use of risperidone in children under 15 years of age for the treatment of manic episodes in bipolar disorders.
Risperidone use is associated with slight increases in body weight and body mass index (BMI). Baseline body weight measurement is recommended before starting treatment, and regular monitoring of body weight should be performed during treatment. Growth changes observed in long-term open-label extension studies were within expected age-related norms. The effect of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.
Due to the potential impact of prolonged hyperprolactinemia on growth and sexual maturation in children, the need for regular clinical monitoring of the patient’s endocrine status, including measurement of height, body weight, monitoring of sexual maturation, menstrual cycle, and other prolactin-dependent phenomena, should be considered.
Results from a small post-marketing observational study showed that patients aged 8–16 years receiving risperidone were on average 3.0–4.8 cm taller than those receiving other antipsychotic drugs. However, data from this study are insufficient to determine whether risperidone affects final adult height, whether the measurement results are directly related to the effect of risperidone on bone growth, whether the underlying disease affects bone growth, or whether this is a result of better disease control leading to greater growth.
During treatment with risperidone, extrapyramidal symptoms and other movement disorders should be regularly monitored.
For dosage recommendations in children, see section “Dosage and administration”.
Somnolence.
During placebo-controlled trials, somnolence was frequently observed in children with autism. Most cases were mild to moderate in severity. Somnolence predominantly occurred at the beginning of treatment, with the highest frequency during the first two weeks, and resolved spontaneously, with a median duration of 16 days. Patients experiencing somnolence may consider adjusting the dosing schedule.
Orthostatic hypotension.
Due to the α1-blocking activity of risperidone, orthostatic hypotension may occur, particularly at the beginning of treatment. Clinically significant hypotension has been observed during the post-marketing period when risperidone was used concomitantly with antihypertensive agents. Risperidone should be used with caution in patients with cardiovascular disorders (such as heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disorders). In such cases, the dose should be gradually adjusted (see section “Dosage and administration”). If hypotension occurs, dose reduction should be considered.
QT interval prolongation.
During clinical trials, QT interval prolongation was not associated with risperidone. In the post-marketing period, very rare cases of QT interval prolongation have been reported. Risperidone, like other antipsychotic agents, should be used with caution in patients with cardiovascular disorders, electrolyte imbalances (hypokalemia, hypomagnesemia), or a family history of QT interval prolongation. Caution is also advised when used concomitantly with drugs that prolong the QT interval.
Leukopenia, neutropenia, agranulocytosis.
Cases of leukopenia, neutropenia, and agranulocytosis have been observed during treatment with antipsychotic agents, including risperidone. Agranulocytosis has been reported very rarely (<1/10,000 patients) in the post-marketing period.
Patients with a history of significant leukocyte reduction or drug-induced leukopenia/neutropenia should be closely monitored during the first few months of treatment. Risperidone should be discontinued if signs of significant leukocyte reduction occur and no other cause is identified.
Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. In cases of severe neutropenia (<1×10⁹/L), risperidone treatment should be discontinued, and leukocyte counts should be monitored until recovery.
Venous thromboembolism.
Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients treated with antipsychotics often have acquired risk factors for venous thromboembolism, all possible risk factors for thromboembolism should be identified before and during risperidone treatment, and appropriate preventive measures should be taken.
Tardive dyskinesia/extrapyramidal symptoms.
Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly of the tongue and/or face), has been reported with drugs that have dopamine receptor antagonist properties. The presence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs and symptoms of tardive dyskinesia occur, discontinuation of all antipsychotic drugs should be considered.
Caution should be exercised when using psychostimulants (e.g., methylphenidate) concomitantly with risperidone, as extrapyramidal symptoms may occur when adjusting the dose of either or both drugs. Gradual discontinuation of psychostimulant therapy is recommended (see section “Interaction with other medicinal products and other forms of interaction”).
Parkinson’s disease and dementia with Lewy bodies.
Physicians should carefully weigh the risks and benefits when prescribing antipsychotic agents, including risperidone, to patients with Parkinson’s disease or dementia with Lewy bodies. The use of risperidone may worsen the course of Parkinson’s disease. Patients with either of these conditions may have an increased risk of neuroleptic malignant syndrome and heightened sensitivity to antipsychotic agents (e.g., confusion, reduced pain sensitivity, postural instability with frequent falls, in addition to extrapyramidal symptoms).
Neuroleptic malignant syndrome.
Rare cases of neuroleptic malignant syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated creatine phosphokinase levels, have been reported with classical neuroleptic drugs. Additional signs include myoglobinuria (rhabdomyolysis) and acute renal failure. If neuroleptic malignant syndrome develops, all antipsychotic drugs, including risperidone, should be discontinued.
Hyperglycemia and diabetes mellitus.
Hyperglycemia, diabetes mellitus, or exacerbation of existing diabetes has been reported during treatment with risperidone. Assessing the relationship between atypical antipsychotics and glucose abnormalities is complicated by the increased risk of diabetes in patients with schizophrenia and the rising prevalence of diabetes in the general population. Thus, the relationship between atypical antipsychotics and hyperglycemia-related adverse reactions is not fully understood, although epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics. All patients receiving atypical antipsychotics should be monitored for symptoms of hyperglycemia and diabetes.
Weight gain.
Significant weight gain has been reported with risperidone use. Body weight monitoring is recommended.
Hyperprolactinemia.
Hyperprolactinemia is a common adverse effect of risperidone treatment. Patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, galactorrhea) should have their prolactin levels monitored.
Tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although a clear link with antipsychotic use has not been established in clinical and epidemiological studies, risperidone should be prescribed with caution in patients with relevant medical history. Risperidone should be used cautiously in patients with hyperprolactinemia and prolactin-dependent tumors, such as prolactinoma of the pituitary gland, or suspected prolactin-dependent tumors, such as epithelial breast tumors.
Priapism.
Priapism may occur during risperidone treatment due to its alpha-adrenergic blocking effect. Cases of priapism have been reported in the post-marketing period.
Body temperature regulation.
Antipsychotic drugs may impair the body’s ability to reduce core body temperature. Appropriate care is recommended for patients receiving risperidone who may be exposed to conditions that could increase core body temperature, such as intense physical exercise, exposure to high environmental temperatures, concomitant therapy with anticholinergic drugs, or dehydration.
Antiemetic effect.
In preclinical studies, risperidone demonstrated antiemetic properties. This property may mask symptoms of drug overdose or conditions such as intestinal obstruction, Reye’s syndrome, or brain tumors.
Seizures.
Risperidone should be used with caution in patients with a history of seizures or other conditions that may potentially lower the seizure threshold.
Intraoperative floppy iris syndrome (IFIS).
Intraoperative floppy iris syndrome has been observed during cataract surgery in patients treated with α1-adrenergic receptor antagonists, including risperidone.
IFIS may increase the risk of ocular surgical complications during and after the procedure. The ophthalmic surgeon should be informed about past or current use of antipsychotic drugs. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risk of discontinuing antipsychotic therapy should be carefully considered.
Hepatic and renal function impairment.
In patients with hepatic or renal impairment, half of the initial and maintenance dose is recommended (see section “Dosage and administration”).
The product contains aspartame (E 951), a phenylalanine derivative, which may be harmful to patients with phenylketonuria.
Use during pregnancy or breastfeeding.
Pregnancy.
Controlled studies in pregnant women have not been conducted. Although teratogenic effects were not observed in animal studies, an indirect effect on prolactin levels was noted.
Newborns exposed to antipsychotic agents (including risperidone) during the third trimester of pregnancy are at risk of developing reversible extrapyramidal symptoms and/or withdrawal syndrome. These symptoms include agitation, abnormally increased or decreased muscle tone, tremor, somnolence, respiratory disturbances, or feeding difficulties. These complications may vary in severity. In some cases, symptoms resolve spontaneously over time; in others, monitoring in an intensive care unit or prolonged hospitalization may be required.
Risperidone is not recommended during pregnancy except in life-threatening situations. If discontinuation of risperidone is necessary during pregnancy, it should not be stopped abruptly.
Breastfeeding.
In animal studies, risperidone and 9-hydroxyrisperidone were found to pass into milk. Observations suggest that risperidone and 9-hydroxyrisperidone may also pass into human breast milk. In individual cases, 4.3% of the maternal dose, as the active antipsychotic fraction of the active substance, was detected in breast milk. If treatment with the drug is necessary, breastfeeding should be discontinued.
Ability to affect reaction speed when driving or operating machinery.
Risperidone may have a slight or moderate effect on the ability to drive due to its potential impact on the nervous system and visual organs (see section “Adverse reactions”). During treatment, patients should refrain from driving or operating machinery until their individual sensitivity to the drug is known.
Method of Administration and Dosage
Risperidone should be administered orally, independently of food intake.
Since the tablets are orodispersible, they should be carefully removed with dry hands directly from the blister immediately before use, placed under the tongue, and, if necessary, taken with water.
Usual Dosage
Risperidone may be administered once or twice daily. Doses exceeding 8 mg should be divided into two administrations (morning and evening). Food intake does not affect the absorption of risperidone.
Gradual discontinuation of treatment is recommended. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia, have been very rarely observed after abrupt discontinuation of high doses of antipsychotics. Recurrence of psychotic symptoms may also occur, and cases of involuntary movements (e.g., akathisia, dystonia, and dyskinesia) have been reported.
Schizophrenia and Other Psychiatric Disorders
Adults
Risperidone may be prescribed once or twice daily.
Treatment should be initiated at 2 mg of risperidone per day; on the second day, the dose may be increased to 4 mg. Thereafter, the dose may be maintained unchanged or, if necessary, further individual dose 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 reduced initial dose.
Doses exceeding 10 mg per day have not demonstrated higher efficacy compared to lower doses but may lead to the occurrence of extrapyramidal symptoms. Doses exceeding 16 mg per day have not been studied for safety and must not be used.
If additional sedation is required, a benzodiazepine may be co-administered.
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.
Manic Episodes in Bipolar Disorders
Adults and children aged 15 years and older
The recommended initial dose of risperidone is 2 mg once daily, in the evening. The dose may be individually increased by increments of 1 mg/day no more frequently than every 24 hours. The recommended dose range is 2 to 6 mg per day.
As with other forms of symptomatic treatment, doses should be periodically reviewed and adjusted throughout long-term therapy. There are no data on the efficacy of risperidone in the treatment of acute bipolar mania beyond 12 weeks. If risperidone is used in combination with mood stabilizers, therapy may be discontinued earlier, as therapeutic effect may be expected within the first weeks of treatment. Even after a response to treatment is achieved, the possibility of recurrent depressive symptoms due to the nature of the disease and adverse reactions of concomitant medications, including risperidone, should be considered.
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 in elderly patients, caution is recommended.
Short-term Treatment of Marked Aggression or Severe Psychiatric Symptoms 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. The optimal dose for most patients is 0.5* mg twice daily. However, for some patients, the effective dose may be increased to 1 mg twice daily. After achieving the optimal dose, once-daily administration of the total daily dose may be considered.
As with other forms of symptomatic treatment, doses should be periodically reviewed and adjusted throughout long-term therapy.
Discontinuation of risperidone treatment should occur no later than three months after initiation of therapy. Re-initiation of treatment may only be considered if behavioral disturbances recur.
*When prescribing doses of 0.25 mg and 0.5 mg, risperidone formulations allowing such dosing should be used.
Symptomatic Treatment of Social Behavior Disorders or Aggressive Behavior
Patients with body weight ≥ 50 kg
The recommended initial dose is 0.5 mg once daily. If necessary, the dose should be adjusted by adding 0.5* mg once daily no more frequently than every other day. The optimal dose for most patients is 1 mg once daily. However, for some patients, a dose of no more than 0.5* mg once daily may be sufficient to achieve a positive effect, while others may require 1.5* mg once daily.
Patients with body weight < 50 kg
The recommended initial dose is 0.25* mg once daily. If necessary, the dose may be adjusted by adding 0.25* mg once daily no more frequently than every other day. The optimal dose for most patients is 0.5* mg once daily. However, for some patients, no more than 0.25* mg once daily may be sufficient 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 requires periodic review and dose adjustment throughout the course of therapy.
There is no experience with the use of risperidone for symptomatic treatment of social behavior disorders or aggressive behavior in children under 5 years of age.
*When prescribing doses of 0.25 mg, 0.5 mg, 0.75 mg, or 1.5 mg, risperidone formulations allowing such dosing should be used.
Autism (Children Aged 5 Years and Older)
The dose should be individually adjusted based on the patient's condition and clinical response.
Patients with body weight < 50 kg
The recommended initial dose is 0.25** mg once daily. From day 4, the dose may be increased by 0.25** mg. The dose of 0.5** mg should be maintained, and clinical response should be evaluated on day 14. Further dose increases of 0.25** mg at 2-week intervals may be considered only for patients with insufficient clinical response.
Patients with body weight ≥ 50 kg
The recommended initial dose is 0.5** mg once daily. From day 4, the dose may be increased by 0.5** mg. The dose of 1 mg should be maintained, and clinical response should be evaluated on day 14. Further dose increases of 0.5** mg at 2-week intervals may be considered only for patients with insufficient clinical response.
Risperidone doses for children with autism (daily dose in mg/day)
| Body weight |
Initial dose (days 1–3) |
Recommended maintenance dose (days 4–14+) |
Dose escalation (if needed) |
Dose range |
| < 50 kg |
0.25 mg |
0.5 mg |
+0.25 mg every ≥ 2 weeks |
< 20 kg: 0.5–1.25 mg ≥ 20 kg: 0.5–2.5 mg* |
| ≥ 50 kg |
0.5 mg |
1.0 mg |
+0.5 mg every ≥ 2 weeks |
1.0–2.5 mg* |
* Patients with body weight above 45 kg may require higher doses; the maximum dose used in clinical trials was 3.5 mg/day.
**When prescribing doses of 0.25 mg, 0.5 mg, 0.75 mg, or 1.5 mg, risperidone formulations allowing such dosing should be used.
Risperidone can be administered once or twice daily.
For patients who experience somnolence after taking the medication, it is preferable to administer the daily dose of risperidone at bedtime or in two divided doses. During clinical trials, approximately two-thirds of children with autism reported weakness, particularly during the initial phase of treatment.
Once an adequate clinical response is achieved, consideration should be given to gradually reducing the dose to achieve the optimal balance between clinical efficacy and safety.
Available data from controlled clinical trials are insufficient to determine the recommended duration of risperidone treatment in patients with autism. Therefore, an experienced specialist should carefully monitor the patient's condition.
In case of severe adverse reactions (e.g., extrapyramidal disorders, tardive dyskinesia, or uncontrolled weight gain), the dose of risperidone should be reduced or treatment discontinued.
There is no experience with the use of risperidone for symptomatic treatment of autism in children under 5 years of age.
Patients with hepatic and renal impairment.
In patients with impaired renal function, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with impaired hepatic function, plasma concentrations of the free fraction of risperidone are increased.
Regardless of the indication, these patients should receive half the initial and maintenance dose, and dose titration should be slower.
Risperidone should be used with caution in this patient population.
Switching from therapy with other antipsychotics.
If clinically justified, it is recommended to gradually discontinue previous antipsychotic treatment when initiating risperidone therapy. When switching from depot antipsychotic formulations, risperidone treatment should be initiated instead of the next scheduled injection. The need for continuing current antiparkinsonian medication should be periodically assessed.
Children.
Risperidone is indicated for the treatment of disorders of social behavior or aggressive behavior, as well as autistic disorders in children aged 5 years and older; for the treatment of manic episodes in bipolar disorder in children aged 15 years and older.
Overdose.
Symptoms.
Signs and symptoms observed in overdose are the known adverse reactions to the drug, but in an intensified form: somnolence and sedation, tachycardia, and arterial hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported in cases of overdose. Atrial flutter associated with risperidone overdose in combination with paroxetine has been reported.
In cases of acute overdose, the possibility of ingestion of multiple drugs should be considered.
Treatment.
Maintain and ensure airway patency to provide adequate ventilation and oxygenation. Administration of activated charcoal together with a laxative should be considered within one hour of drug ingestion. Cardiovascular monitoring, including continuous ECG recording to detect possible arrhythmias, is indicated. Risperidone has no specific antidote. Therefore, appropriate supportive measures should be taken. In cases of acute overdose, potential drug interactions involving multiple medications should be evaluated. Arterial hypotension and vascular collapse should be treated with measures such as intravenous fluids and/or sympathomimetic agents. In the event of acute extrapyramidal symptoms, anticholinergic medications should be administered. Continuous medical observation should be maintained until the patient has fully recovered.
Adverse reactions
The most commonly reported adverse reactions (frequency ≥ 10%) are parkinsonism, sedation/somnolence, headache, and insomnia. Parkinsonism and akathisia are dose-dependent adverse reactions.
The adverse reactions listed below include those reported during clinical trials and in the post-marketing period. Frequency of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and not known (frequency cannot be estimated from the available data).
Within each category, adverse reactions are listed in order of decreasing frequency.
| Infections and infestations |
|
| Common |
pneumonia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, ear infections, influenza |
| Uncommon |
respiratory tract infections, cystitis, eye infections, tonsillitis, onychomycosis, cellulitis, localized infection, viral infection, acarodermatitis |
| Rare |
infection |
| Blood and lymphatic system disorders |
|
| Uncommon |
neutropenia, decreased white blood cell count, thrombocytopenia, anemia, decreased hematocrit, increased eosinophils |
| Rare |
agranulocytosis |
| Immune system disorders |
|
| Uncommon |
hypersensitivity |
| Rare |
anaphylactic reaction |
| Endocrine system disorders |
|
| Common |
hyperprolactinemia |
| Rare |
disturbance of antidiuretic hormone secretion, presence of glucose in urine |
| Metabolism and nutrition disorders |
|
| Common |
weight gain, increased appetite, decreased appetite |
| Uncommon |
diabetes mellitusb, hyperglycemia, polydipsia, weight loss, anorexia, increased cholesterol level |
| Rare |
water intoxication, hypoglycemia, hyperinsulinism, increased blood triglycerides |
| Very rare |
diabetic ketoacidosis |
| Psychiatric disorders |
|
| Very common |
insomniad |
| Common |
sleep disorders, agitation, depression, anxiety |
| Uncommon |
mania, confusion, decreased libido, restlessness, night terrors |
| Rare |
catatonia, somnambulism, sleep-related eating disorder, blunted affect, anorgasmia |
| Nervous system disorders |
|
| Very common |
sedation/somnolence, parkinsonismd, headache |
| Common |
akathisiad, dystoniad, dizziness, dyskinesiad, tremor |
| Uncommon |
late dyskinesia, cerebral ischemia, unresponsiveness, loss of consciousness, depressed level of consciousness, seizuresd, syncope, psychomotor hyperactivity, balance disorders, coordination disturbances, postural dizziness, attention disturbances, dysarthria, taste disturbances, hypoesthesia, paresthesia |
| Rare |
malignant neuroleptic syndrome, cerebrovascular disorders, diabetic coma, rhythmic head bobbing |
| Eye disorders |
|
| Common |
blurred vision, conjunctivitis |
| Uncommon |
photophobia, dry eyes, increased lacrimation, eye redness |
| Rare |
glaucoma, eye movement disorders, rotatory nystagmus, eyelid crusting, intraoperative floppy iris syndrome |
| Ear and labyrinth disorders |
|
| Uncommon |
vertigo, tinnitus, ear pain |
| Cardiac disorders |
|
| Common |
tachycardia |
| Uncommon |
atrial fibrillation, atrioventricular block, cardiac conduction disorders, QT interval prolongation on electrocardiogram, bradycardia, electrocardiogram abnormalities, palpitations |
| Rare |
sinus arrhythmia |
| Not known |
postural orthostatic tachycardia syndrome |
| Vascular disorders |
|
| Common |
arterial hypertension |
| Uncommon |
hypotension, orthostatic hypotension, flushing |
| Rare |
pulmonary embolism, venous thrombosis |
| Respiratory system disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening airway patency, wheezing, stridor, dysphonia, respiratory disturbances |
| Rare |
sleep apnea syndrome, hyperventilation |
| Gastrointestinal disorders |
|
| Common |
abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache |
| Uncommon |
fecal incontinence, fecaloma, gastroenteritis, dysphagia, abdominal distension |
| Rare |
pancreatitis, gastrointestinal tract 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, seborrheic dermatitis, skin disorders, skin injury |
| Rare |
drug eruption, dandruff |
| Very rare |
angioedema |
| Musculoskeletal and connective tissue disorders |
|
| Common |
muscle spasms, musculoskeletal pain, back pain, arthralgia |
| Uncommon |
increased creatine phosphokinase, posture abnormalities, joint stiffness, joint swelling, muscle weakness, neck pain |
| Rare |
rhabdomyolysis |
| Renal and urinary disorders |
|
| Common |
urinary incontinence |
| Uncommon |
polyuria, urinary retention, dysuria |
| Pregnancy, puerperium and perinatal conditions |
|
| Very rare |
extrapyramidal symptoms and/or drug withdrawal syndrome in newborns |
| Reproductive system and breast disorders |
|
| Uncommon |
erectile dysfunction, ejaculation disorder, amenorrhea, menstrual cycle disturbanced, gynecomastia, galactorrhea, sexual dysfunction, breast pain, vaginal discharge |
| Rare |
priapism, menstrual delay, breast engorgement, breast enlargement, breast discharge |
| General disorders |
|
| Common |
edemad, fever, chest pain, asthenia, fatigue, pain |
| Uncommon |
facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, fever, unusual sensations, discomfort |
| Rare |
hypothermia, decreased body temperature, cold sensation in limbs, drug withdrawal syndrome, induration |
| Injury and poisoning |
|
| Common |
falls |
| Uncommon |
post-surgical pain |
a Hyperprolactinaemia may in some cases lead to gynaecomastia, menstrual disorders, amenorrhoea, anovulation, galactorrhoea, impaired fertility, decreased libido, and erectile dysfunction.
b During placebo-controlled trials, diabetes mellitus was reported in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients treated with risperidone.
c Not observed in clinical studies of risperidone, but identified during post-marketing surveillance.
d Extrapyramidal disorders include: parkinsonism (hypersalivation, muscle rigidity, parkinsonism, sialorrhoea, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like facies, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, myoclonus), and dystonia.
Dystonia includes dystonia, hypertonia, torticollis, involuntary muscle contractions, myogenic contractures, blepharospasm, eye movement disorders, tongue paralysis, tic (in the facial area), laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, trismus. A broader list of symptoms is included, not all of which necessarily have an extrapyramidal origin. Insomnia includes difficulty falling asleep, intrasomnic disturbances. Seizures include generalized tonic-clonic seizures. 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 adverse reaction profiles of these substances (including oral and injectable formulations) are similar. In addition to the adverse reactions listed above, postural orthostatic tachycardia syndrome has been reported with paliperidone use, which may also possibly occur with risperidone.
Adverse reactions common to antipsychotic medicinal products
QT interval prolongation
As with other antipsychotics, QT interval prolongation has been reported during the post-marketing period with risperidone. Other cardiac adverse reactions associated with QT prolongation have also been reported with antipsychotic agents, such as ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden cardiac death, cardiac arrest, and atrial flutter/fibrillation.
Venous thromboembolism
Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported during antipsychotic treatment.
Weight gain
Comparison of the number of patients treated with risperidone versus placebo who experienced a weight gain of 7% or more in placebo-controlled trials lasting 6 to 8 weeks showed a statistically significant difference in the frequency of weight gain in the risperidone group (18%) compared to the placebo group (9%). In three-week placebo-controlled trials in adult patients with acute mania, the frequency of weight gain ≥7% was similar in the risperidone group (2.5%) and the placebo group (2.4%), and slightly higher in the active control group (3.5%).
In paediatric populations with behavioural disorders, during long-term studies, patients gained on average 7.3 kg after 12 months of treatment. The expected annual weight gain in children with normal body weight aged 5–12 years is 3 to 5 kg. Starting at age 12, weight gain in girls remains at 3 to 5 kg per year, while boys gain on average 5 kg per year.
Additional information on specific patient categories
Adverse reactions reported more frequently in elderly patients with dementia or in children compared to adults are described below.
Elderly patients with dementia
Transient ischaemic attack and cerebrovascular disorders were adverse reactions reported during clinical trials with frequencies of 1.4% and 1.5%, respectively, in elderly patients with dementia. Additionally, the following adverse reactions were reported with a frequency ≥5% in elderly patients with dementia and at least twice as high as in other adult patient groups: urinary tract infections, peripheral oedema, lethargy, and cough.
Children
Overall, the expected adverse reactions in children are similar to those in adults in terms of frequency, type, and severity.
Adverse reactions observed in children (aged 5 to 17 years) with a frequency ≥5% and at least twice as high as in adult patients: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhoea, and enuresis.
The long-term impact of risperidone treatment on sexual maturation and growth has not been fully studied (see section "Special warnings and precautions for use").
Shelf life.
2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Packaging.
10 tablets per blister, 2 or 6 blisters per cardboard pack.
Prescription status.
Prescription only.
Manufacturer.
Kusum Healthcare Pvt Ltd.
Manufacturer's address and location of operations.
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.