Rosemide®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROSEMIDE® (ROSEMIDE®)
Composition:
Active substance: risperidone;
1 ml of solution contains risperidone 1 mg;
Excipients: tartaric acid, benzoic acid (E 210), sodium hydroxide, purified water.
Pharmaceutical form. Oral solution.
Main physicochemical properties: clear, colorless solution.
Pharmacotherapeutic group. Antipsychotics. ATC code N05A X08.
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 shows no 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 suppression of motor activity and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism of serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.
Pharmacokinetics.
Risperidone in orally disintegrating tablets and risperidone in film-coated tablets are bioequivalent to oral solution of risperidone.
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 maximum plasma concentration within 1–2 hours; in elderly patients, within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV=25%). Relative bioavailability after oral administration of tablet formulations of risperidone is 94% (CV=10%) compared to the oral solution. Food does not affect drug absorption; therefore, risperidone can be administered independently of food intake. Absolute bioavailability is 66% in fast metabolizers and 82% in slow metabolizers.
Distribution
Risperidone is rapidly distributed in the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and acid α1-glycoprotein. Risperidone is 90% bound to plasma proteins; 9-hydroxyrisperidone is 77% bound. Steady-state concentrations of risperidone in the body are achieved within 1 day in most patients. Steady-state concentrations of 9-hydroxyrisperidone are achieved 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 fast metabolizers of CYP2D6, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, the conversion is much slower. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in fast metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both fast and slow metabolizers of cytochrome CYP2D6.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. One week after administration, 70% of the dose is excreted in urine and 14% in feces. The concentration of risperidone and 9-hydroxyrisperidone in urine equals 35–45% of the administered dose. The remainder consists of inactive metabolites. After oral administration in patients with psychosis, the elimination half-life is approximately 3 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, 34 hours.
Linearity
Plasma concentrations of risperidone are proportional to the dose (within the therapeutic dose range).
Elderly patients and patients with renal or hepatic impairment
A pharmacokinetic study of single-dose administration in elderly patients demonstrated that in these patients, the concentration of the active antipsychotic fraction is 43% higher, the elimination half-life is 38% longer, and the clearance of the active antipsychotic fraction is 30% lower.
In adult patients with impaired renal function, the clearance of the active fraction was ~48% of that in adults without renal impairment. In adult patients with severe renal impairment, clearance was ~31% of that in adults without renal impairment. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (approximately 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in young adults). In patients with hepatic insufficiency, normal plasma concentrations of risperidone were observed, but the mean value of the free fraction of risperidone in plasma was increased by 37.1%.
After oral administration, the clearance and elimination half-life of risperidone and the active antipsychotic fraction in patients with moderate 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 on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Clinical characteristics.
Indications.
- Treatment of schizophrenia;
- treatment of moderate to severe manic episodes in bipolar disorders;
- short-term treatment (up to 6 weeks) of marked aggression in patients with moderate to severe Alzheimer's type dementia when there is a risk of harm to self or others and when there is no response to non-pharmacological treatment methods (see sections "Dosage and administration" and "Special precautions");
- short-term symptomatic treatment (up to 6 weeks) of marked aggression in behavioral disorders in children aged 5 years and adolescents with below-average intellectual development or intellectual disability diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological treatment should be an integral part of a comprehensive treatment program including psychological support and educational measures. It is recommended that Rosamid® 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 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 symptoms: parkinsonism, visual hallucinations, postural instability).
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions.
Medicinal products that prolong the QT interval.
As with other antipsychotics, caution should be exercised when administering risperidone with medicinal products that prolong the QT interval, for example, 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 effect
During the post-marketing period, cases of clinically significant hypotension were observed with concomitant use of risperidone and antihypertensive medicinal products.
Psychostimulants
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 modulate CYP2D6 activity, or potent inhibitors or inducers of CYP3A4 and/or P-gp, may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.
Potent CYP2D6 inhibitors
Concomitant use of risperidone with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but less so the concentration of the active antipsychotic fraction. Higher doses of a potent CYP2D6 inhibitor may increase the concentration of the active antipsychotic fraction of risperidone (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are expected to affect plasma concentrations of risperidone similarly. At the start of concomitant therapy, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the risperidone dose.
Inhibitors of CYP3A4 and P-gp
Concomitant use of risperidone with potent inhibitors of CYP3A4 and/or P-gp may significantly increase plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation of concomitant therapy, and upon discontinuation of itraconazole or other potent inhibitors of CYP3A4 and/or P-gp, the physician should review the risperidone dose.
Inducers of CYP3A4 and P-gp
Concomitant use of risperidone with potent inducers of CYP3A4 and/or P-gp may reduce plasma concentrations of the active antipsychotic fraction of risperidone. At the start of therapy, and upon discontinuation of carbamazepine or other strong inducers of CYP3A4/P-gp, the physician should review the risperidone dose. The effect of CYP3A4 inducers depends on duration, with maximum impact reached at least 2 weeks after initiation of treatment. Accordingly, after discontinuation of the inducer, CYP3A4 induction may persist for at least 2 weeks.
Medicinal products with high plasma protein binding
When risperidone is used concomitantly with other medicinal products that are highly bound to plasma proteins, clinically significant displacement of either drug from the protein fraction has not been observed. When used concomitantly with such a medicinal product, the prescribing information of that product regarding metabolic pathways and need for dose adjustment should be consulted.
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 agents
- Erythromycin, a moderate inhibitor of CYP3A4 and inhibitor of P-gp, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Rifampicin, a potent inducer of CYP3A4 and inducer of P-gp, reduces plasma concentrations of the active antipsychotic fraction.
Cholinesterase inhibitors
- Donepezil and galantamine, substrates of CYP2D6 and CYP3A4, do not demonstrate clinically significant effects on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Antiepileptic agents
- Carbamazepine, a potent inducer of CYP3A4 and inducer of P-gp, has shown an effect in reducing plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may be observed with phenytoin and phenobarbital, which are also inducers of hepatic enzymes CYP3A4 and P-gp.
- Topiramate moderately reduces the bioavailability of risperidone and does not affect the bioavailability of the active antipsychotic fraction. It is unlikely that this interaction will cause a clinically significant effect.
Antifungal agents
- Itraconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg daily, increases plasma concentrations of the active antipsychotic fraction by approximately 70% when used concomitantly with risperidone at doses of 2 to 8 mg daily.
- Ketoconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg daily, increases plasma concentrations of risperidone and decreases concentrations of 9-hydroxyrisperidone.
Antipsychotic agents
- Phenothiazines may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction.
Antiviral agents
- Protease inhibitors: study data are lacking; since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and ritonavir-boosted protease inhibitors may increase plasma concentrations of the active antipsychotic fraction of risperidone.
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 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.
Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants
- Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but less so the concentration of the active antipsychotic fraction.
- Paroxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but (at doses up to 20 mg daily) less so the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction.
- Tricyclic antidepressants may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at doses up to 100 mg daily, do not cause clinically significant changes in the concentration of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg daily may increase the concentration of the active antipsychotic fraction of risperidone.
Effect of risperidone on the pharmacokinetics of other medicinal products
Antiepileptic agents
- Risperidone has no clinically significant effect on the pharmacokinetics of valproate or topiramate.
Antipsychotic agents
- Aripiprazole, a substrate of CYP2D6 and CYP3A4: oral or injectable formulations of risperidone do not affect the pharmacokinetics of aripiprazole or its active metabolite dehydro-aripiprazole.
Cardiac glycosides
- Risperidone has no clinically significant effect on the pharmacokinetics of digoxin.
Lithium
- Risperidone has no clinically significant effect on the pharmacokinetics of lithium.
Concomitant use of risperidone with furosemide
See section "Special precautions" regarding increased mortality in elderly patients with dementia when used concomitantly with furosemide.
Special precautions for use.
Geriatric patients with dementia
Increased mortality
An increased mortality rate has been observed in elderly patients with dementia treated with atypical antipsychotic agents compared to placebo-treated patients in a meta-analysis of 17 controlled trials of atypical antipsychotic agents, including risperidone. In a placebo-controlled trial using risperidone in this patient population, the incidence of death was 4.0% compared to 3.1% in the placebo group. The odds ratio (95% confidence interval) was 1.21 (0.7; 2.1). The mean age of patients who died was 86 years (range: 67–100 years).
Data from two large observational studies suggest that elderly patients with dementia treated with conventional (typical) antipsychotic agents have a slightly increased risk of death compared to patients not receiving antipsychotics. Based on available data, the exact level of this risk cannot be determined, and the reason for the increased risk is unknown.
Concomitant use with furosemide
In a placebo-controlled trial in elderly patients with dementia, an increased mortality rate was observed when risperidone was used concomitantly with furosemide (7.3%; mean age 89 years, range: 75–97 years) compared to patients treated 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 among patients treated concomitantly with risperidone and furosemide was observed in two out of four clinical trials. No increased mortality rate was observed in patients who received risperidone concomitantly with other diuretics.
The pathophysiological mechanisms underlying this observation have not been established. The cause of death was not uniform. However, particular caution should be exercised when prescribing this combination, and the risks and benefits of this combination or combinations with other potential diuretics should be carefully evaluated before administration. No increased mortality was observed in patients who received risperidone with other diuretics. Regardless of treatment, dehydration was a common risk factor for mortality and should be carefully monitored in patients with dementia.
Cerebrovascular adverse reactions (CVAE)
In placebo-controlled clinical trials, elderly patients with dementia treated with risperidone showed a higher incidence (approximately three times) of cerebrovascular adverse events (strokes and transient ischemic attacks), some fatal, compared to placebo recipients (mean age: 85 years; range: 73–97 years).
Pooled data from six placebo-controlled trials involving elderly patients with dementia (aged 65 years and older) demonstrated cerebrovascular disorders (serious and non-serious, combined) in 3.3% (33/1009) of patients treated with risperidone compared to 1.2% (8/712) of patients receiving placebo. The odds ratio (95% CI) between the risperidone and placebo groups was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk of CVAE for other antipsychotic agents or other patient populations cannot be ruled out. Risperidone should be used with caution in patients with risk factors for stroke.
The risk of cerebrovascular adverse 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. The risks and benefits of prescribing risperidone to elderly patients with dementia, particularly the risk of stroke, should be carefully weighed.
Patients and caregivers should be instructed to immediately report signs of possible cerebrovascular disorders, such as sudden weakness, facial, arm, or leg numbness, speech disturbances, or visual disturbances. All treatment options, including discontinuation of risperidone therapy, should be promptly considered.
For persistent aggression in patients with moderate to severe Alzheimer’s disease, risperidone should be prescribed only for short-term use as an adjunct to non-pharmacological interventions that have shown limited or no efficacy, and only if there is no potential risk of harm to self or others.
During treatment, patients should be regularly assessed, and the need for continued therapy should be re-evaluated.
Orthostatic hypotension
Due to the α1-blocking activity of risperidone, particularly at the beginning of treatment, orthostatic hypotension may occur. Clinically significant hypotension has been observed during post-marketing experience with concomitant use of risperidone and antihypertensive agents. Risperidone should be used with caution in patients with cardiovascular disorders (such as heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disorders). In such cases, dosage should be gradually adjusted (see section "Dosage and administration"). If hypotension occurs, dose reduction should be considered.
Leukopenia, neutropenia, agranulocytosis
Cases of leukopenia, neutropenia, and agranulocytosis have been reported during treatment with 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 medication-induced leukopenia/neutropenia should be closely monitored during the first few months of treatment, and risperidone should be discontinued if signs of significant leukocyte reduction occur in the absence of other causes.
Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. In cases of severe neutropenia (< 1 × 10⁹/L), risperidone treatment should be discontinued, and leukocyte counts should be monitored until recovery.
Tardive dyskinesia/extrapyramidal symptoms
Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly of the tongue and/or face), has been observed with drugs possessing dopamine receptor antagonist properties. The occurrence of extrapyramidal symptoms is a risk factor for developing tardive dyskinesia. If signs or symptoms of tardive dyskinesia appear, discontinuation of all antipsychotic agents should be considered.
Caution is advised when co-administering psychostimulants (e.g., methylphenidate) with risperidone, as extrapyramidal symptoms may occur during dose adjustment of either or both agents. Gradual discontinuation of psychostimulant therapy is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Neuroleptic malignant syndrome
Rare cases of neuroleptic malignant syndrome have been reported with classical neuroleptic agents, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated creatine phosphokinase levels. Additional features include myoglobinuria (rhabdomyolysis) and acute renal failure. In the event of neuroleptic malignant syndrome, all antipsychotic agents, including risperidone, should be discontinued.
Parkinson’s disease and dementia with Lewy bodies
Physicians should consider the risks associated with using antipsychotic agents, including risperidone, in patients with Parkinson’s disease or dementia with Lewy bodies (see section "Contraindications"). Risperidone use may worsen the course of Parkinson’s disease. Patients with either of these conditions may have an increased risk of neuroleptic malignant syndrome and increased sensitivity to antipsychotic agents (e.g., confusion, reduced pain sensitivity, postural instability with frequent falls, in addition to extrapyramidal symptoms).
Hypoglycemia and diabetes mellitus
Cases of hyperglycemia, new-onset diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with risperidone.
In some cases, prior excessive body weight, which may be a triggering factor, has been reported. Very rarely, ketoacidosis and, less frequently, diabetic coma have been reported. Appropriate clinical monitoring according to antipsychotic use guidelines is recommended. Patients receiving any atypical antipsychotic agents, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, weakness), and patients with diabetes should be regularly evaluated for worsening glucose control.
Weight gain
Significant weight gain has been reported with risperidone use. Weight monitoring is recommended.
Hyperprolactinemia
Hyperprolactinemia is a common adverse effect of risperidone treatment. Patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, galactorrhea) should be monitored for prolactin levels.
Tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although a clear association with antipsychotic use has not been established in clinical and epidemiological studies, risperidone should be prescribed with caution in patients with a relevant history. Risperidone should be used cautiously in patients with hyperprolactinemia and in those with prolactin-dependent tumors.
QT interval prolongation
QT interval prolongation has been reported very rarely in the post-marketing period. As with other antipsychotic agents, risperidone should be used with caution in patients with known cardiovascular disorders, family history of QT prolongation, bradycardia, or electrolyte imbalances (hypokalemia, hypomagnesemia), as these may increase the risk of arrhythmogenic effects. Caution is also required when risperidone is used concomitantly with other medicinal products that prolong the QT interval.
Seizures
Risperidone should be used with caution in patients with a history of seizures or other conditions that may potentially lower the seizure threshold.
Priapism
Priapism may occur during risperidone treatment due to its alpha-adrenergic blocking effect.
Body temperature regulation
Antipsychotic agents may impair the body's ability to reduce core body temperature. Appropriate care is recommended for patients receiving risperidone who may be exposed to conditions that may elevate core body temperature, such as intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic agents, or dehydration.
Antiemetic effect
Preclinical studies have shown risperidone to have an antiemetic effect. This property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye’s syndrome, or brain tumors.
Hepatic and renal function impairment
Patients with impaired renal function have reduced ability to eliminate the active antipsychotic fraction of the drug compared to adults with normal renal function. In patients with impaired hepatic function, increased plasma concentration of the free fraction of risperidone is observed (see section "Dosage and administration").
Venous thromboembolism
Cases of venous thromboembolism have been reported with antipsychotic agents. 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.
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 surgery. Ophthalmic surgeons should be informed of current or past use of antipsychotic agents. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risk of discontinuing antipsychotic therapy should be weighed.
Children
Before prescribing risperidone 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 environmental responses, should be evaluated.
The sedative effect of risperidone should be carefully monitored in pediatric patients due to potential effects on learning ability. Adjusting the timing of risperidone administration may improve the impact of sedation on attention in children and adolescents.
Risperidone use is associated with moderate increases in body weight and body mass index (BMI). Baseline weight measurement before treatment initiation and regular weight monitoring during treatment are recommended. Growth changes observed in long-term, open-label extension studies were within expected age-related norms. The effect of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.
Due to the potential effects of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including height, weight, sexual maturation, menstrual cycle, and other prolactin-dependent phenomena, should be considered.
Results from a small post-marketing observational study showed that patients aged 8–16 years receiving risperidone were on average 3.0–4.8 cm taller than those receiving other antipsychotic agents. These data are insufficient to determine whether risperidone affects final adult height, whether the growth measurements are directly influenced by risperidone’s effect on bone growth, whether the underlying disease affects bone growth, or whether the result reflects better disease control leading to greater growth.
During risperidone treatment, extrapyramidal symptoms and other movement disorders should be regularly monitored.
For dosage recommendations in children, see section "Dosage and administration".
Excipients
This medicinal product contains 1 mmol of sodium per 1 ml of oral solution. Caution is advised when administering to patients on a sodium-restricted diet.
Use during pregnancy or breastfeeding
Pregnancy
No controlled studies have been conducted in pregnant women. Although teratogenic effects were not observed in animal studies, other signs of reproductive toxicity were noted. The potential risk in humans is unknown.
Newborns whose mothers used 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, unusual increase or decrease in muscle tone, tremor, somnolence, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be carefully monitored.
Risperidone is not recommended during pregnancy except in cases of essential medical need. If risperidone treatment must be discontinued during pregnancy, it should not be stopped abruptly.
Breastfeeding
In animal studies, risperidone and 9-hydroxyrisperidone were excreted in milk. Observations suggest that risperidone and 9-hydroxyrisperidone may also be excreted in human breast milk. There are no data on adverse reactions in breastfed infants. Therefore, the benefits of breastfeeding and the potential risks to the infant should be carefully weighed.
Fertility
Like other medicinal products that are dopamine D2-receptor antagonists, risperidone increases prolactin levels.
Hyperprolactinemia may suppress gonadotropin-releasing hormone production in the hypothalamus, leading to reduced pituitary gonadotropin secretion. This may negatively affect reproductive function in both women and men due to impaired gonadal steroidogenesis.
No relevant effects were observed in preclinical studies.
Ability to influence reaction speed when driving or operating machinery
Risperidone may have a slight or moderate effect on the ability to drive due to its potential effects on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving and operating machinery until their individual response to the drug is known.
Method of Administration and Dosage
Dosage
Schizophrenia
Adults
Rosamid® can be administered once or twice daily.
Treatment should be initiated at 2 mg per day; on the second day the dose may be increased to 4 mg. After this, the dose may be maintained unchanged or, if necessary, further individual dose adjustments may be continued.
The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or lower initial and maintenance doses.
Doses exceeding 10 mg of risperidone per day have not demonstrated greater efficacy compared to lower doses, but may cause extrapyramidal symptoms.
The safety of doses exceeding 16 mg per day has not been studied.
Elderly patients (aged 65 years and older)
The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily.
Children
Use in children (under 18 years of age) is not recommended.
Manic Episodes in Bipolar Disorders
Adults
The recommended initial dose of risperidone 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 per day in patients with manic episodes has not been studied.
As with other forms of symptomatic treatment, long-term use of risperidone should be periodically reviewed and adjusted throughout therapy.
Elderly patients (aged 65 years and older)
The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily. Since experience in elderly patients is limited, caution is recommended when administering the drug.
Children
Use in children (under 18 years of age) is not recommended.
Short-term Treatment of Severe Agitation in Patients with Alzheimer's Type Dementia
The recommended initial dose is 0.25 mg twice daily. If necessary, the dose may be increased by increments of 0.25 mg twice daily no more frequently than every other day. For most patients, the optimal dose is 0.5 mg twice daily. However, for some patients, an effective dose may be 1 mg twice daily.
Rosamid® should not be used for longer than 6 weeks in patients with severe agitation due to Alzheimer's disease. As with other forms of symptomatic treatment, the use of Rosamid® should be periodically reviewed and adjusted throughout therapy.
Short-term Symptomatic Treatment (up to 6 weeks) of Severe Aggression in Behavioral Disorders
Children and Adolescents Aged 5 to 18 Years
Patients with body weight ≥ 50 kg
The recommended initial dose is 0.5 mg once daily. If necessary, the dose should 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, for some patients, 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 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, 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, the use of Rosamid® should be periodically reviewed and adjusted throughout therapy.
Children
Use of the drug is not recommended in children under 5 years of age.
Patients with Hepatic and Renal Impairment
In patients with renal impairment, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with hepatic impairment, 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.
Rosamid® should be used with caution in this patient population.
Method of Administration
Rosamid® is intended for oral administration. Food intake does not affect the absorption of Rosamid®.
At the end of treatment, gradual discontinuation of the medication is recommended. After abrupt discontinuation of high doses of antipsychotics, isolated cases of acute withdrawal symptoms have been observed, including nausea, vomiting, sweating, and insomnia (see section "Adverse Reactions"). Psychotic symptoms may also recur, and cases of involuntary movements (e.g., akathisia, dystonia, and dyskinesia) have been reported.
Switching from Therapy with Other Antipsychotic Agents
If clinically justified, it is recommended to gradually discontinue previous antipsychotic therapy when initiating treatment with Rosamid®. When switching from depot antipsychotic formulations, treatment with Rosamid® should be initiated instead of the next scheduled injection. The need for continued antiparkinsonian therapy should be periodically evaluated.
Rosamid® oral solution is incompatible with most types of tea, including black tea.
Method of Administration of Oral Solution
Dosing is performed using the oral syringe provided in the package.
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Correspondence of Rosumid® dosages in milligrams (mg) and milliliters (ml)
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Children.
Risperidone is used for the treatment of marked aggression in behavioural disorders in children aged 5 years and older.
Overdose.
Symptoms.
Signs and symptoms observed in overdose are the known adverse reactions of the drug, manifested in an exaggerated form: somnolence and sedation, tachycardia and hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported. Torsade de pointes/ventricular fibrillation associated with risperidone overdose in combination with paroxetine has been reported.
In cases of acute overdose, the possibility of ingestion of multiple medicinal products should be considered.
Treatment.
Airway patency should be ensured and maintained to provide adequate ventilation and oxygenation. Administration of activated charcoal together with a laxative should be considered, if not more than one hour has passed since drug intake. 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, the possibility of drug interactions involving multiple agents should be evaluated. 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 agents should be administered. Continuous medical supervision 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 available data).
Within each category, adverse reactions are listed in order of decreasing severity.
| Infections and infestations |
|
| Common |
pneumonia, bronchitis, upper respiratory tract infections, sinusitis, urinary tract infections, ear infections, influenza |
| Uncommon |
respiratory tract infections, cystitis, eye infections, tonsillitis, onychomycosis, cellulitis, localized infection, viral infection, acarodermatitis |
| Rare |
infection |
| Blood and lymphatic system disorders |
|
| Uncommon |
neutropenia, decreased white blood cell count, thrombocytopenia, anemia, decreased hematocrit, increased eosinophil count |
| Rare |
agranulocytosis |
| Immune system disorders |
|
| Uncommon |
hypersensitivity |
| Rare |
anaphylactic reaction |
| Endocrine system disorders |
|
| Common |
hyperprolactinemia |
| Rare |
disorders of antidiuretic hormone secretion, presence of glucose in urine |
| Metabolism and nutrition disorders |
|
| Common |
weight gain, increased appetite, decreased appetite |
| Uncommon |
diabetes mellitus, hyperglycemia, polydipsia, weight loss, anorexia, increased cholesterol level |
| Rare |
water intoxication, hypoglycemia, hyperinsulinism, increased blood triglyceride levels |
| Very rare |
diabetic ketoacidosis |
| Psychiatric disorders |
|
| Very common |
insomnia |
| Common |
sleep disorders, agitation, depression, anxiety |
| Uncommon |
mania, confusion, decreased libido, restlessness, nightmares |
| Rare |
catatonia, somnambulism, sleep-related eating disorder, blunted affect, anorgasmia |
| Nervous system disorders |
|
| Very common |
sedation/somnolence, parkinsonism, headache |
| Common |
akathisia, dystonia, dizziness, dyskinesia, tremor |
| Uncommon |
late dyskinesia, cerebral ischemia, unresponsiveness, loss of consciousness, depressed level of consciousness, seizures, syncope, psychomotor hyperactivity, balance disorders, coordination disturbances, postural dizziness, attention disturbances, dysarthria, taste disturbances, hypoesthesia, paresthesia |
| Rare |
malignant neuroleptic syndrome, cerebrovascular disorders, diabetic coma, rhythmic head bobbing |
| Eye disorders |
|
| Common |
blurred vision, conjunctivitis |
| Uncommon |
photophobia, dry eyes, increased lacrimation, eye redness |
| Rare |
glaucoma, disturbances in eye movement, rotatory nystagmus, eyelid margin 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 disturbances, QT interval prolongation on electrocardiogram, bradycardia, electrocardiogram abnormalities, palpitations |
| Rare |
sinus arrhythmia |
| Vascular disorders |
|
| Common |
arterial hypertension |
| Uncommon |
hypotension, orthostatic hypotension, flushing |
| Rare |
pulmonary embolism, venous thrombosis |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening of 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 obstruction, tongue swelling, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
elevated transaminase levels, elevated gamma-glutamyl transferase levels, elevated liver enzyme levels |
| Rare |
jaundice |
| Skin and subcutaneous tissue disorders |
|
| Common |
rash, erythema |
| Uncommon |
urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin color changes, acne, seborrheic dermatitis, skin disorders, skin injury |
| Rare |
drug eruptions, dandruff |
| Very rare |
angioedema |
| Not known |
Stevens-Johnson syndrome/toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders |
|
| Common |
muscle spasms, musculoskeletal pain, back pain, arthralgia |
| Uncommon |
elevated creatine phosphokinase levels, 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 |
drug withdrawal syndrome in newborns |
| Reproductive system and breast disorders |
|
| Uncommon |
erectile dysfunction, ejaculation disorder, amenorrhea, menstrual cycle disturbances, gynecomastia, galactorrhea, sexual dysfunction, breast pain, vaginal discharge |
| Rare |
priapism, menstrual delay, breast engorgement, breast enlargement, breast discharge |
| General disorders and administration site conditions |
|
| Common |
edema, pyrexia, chest pain, asthenia, fatigue, pain |
| Uncommon |
facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, hot flushes, unusual feelings, discomfort |
| Rare |
hypothermia, decreased body temperature, cold sensation in limbs, drug withdrawal syndrome, induration |
| Injury and poisoning |
|
| Common |
falls |
| Uncommon |
post-surgical pain |
a Hyperprolactinemia in some cases may lead to gynecomastia, menstrual disorders, amenorrhea, anovulation, galactorrhea, impaired fertility, decreased libido, and erectile dysfunction.
b During placebo-controlled studies, diabetes mellitus was reported in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients treated with risperidone.
c Not observed in clinical studies of risperidone but identified during post-marketing surveillance.
d Extrapyramidal disorders include: parkinsonism (hypersalivation, muscle rigidity, parkinsonism, drooling, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like facies, muscle tension, akinesia, nuchal muscle 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, which do not necessarily have extrapyramidal origin. Insomnia includes: difficulty falling asleep, intrasomnic disorder. Seizures include grand mal epileptic seizures. Menstrual disorders include: irregular menstruation, oligomenorrhea. Edema includes: generalized edema, peripheral edema, pitting edema.
Adverse reactions of paliperidone
Paliperidone is an active metabolite of risperidone; therefore, the adverse reaction profiles of these substances (including oral and injectable formulations) are similar. In addition to the adverse reactions listed above, postural orthostatic tachycardia syndrome has been reported with paliperidone use, which may also occur with risperidone.
Cardiac disorders
Postural orthostatic tachycardia syndrome.
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 for risperidone. Other cardiac adverse reactions associated with QT interval prolongation have also been reported with antipsychotic drugs, such as ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and atrial flutter/fibrillation.
Venous thromboembolism
Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported during antipsychotic therapy.
Weight gain
Comparison of the number of patients treated with risperidone versus placebo who experienced a weight gain of 7% or more in placebo-controlled trials lasting 6 to 8 weeks showed a statistically significant higher incidence of weight gain in the risperidone group (18%) compared to the placebo group (9%). In 3-week placebo-controlled trials in adult patients with acute mania, the incidence of weight gain ≥7% was comparable between the risperidone group (2.5%) and the placebo group (2.4%), and slightly higher in the active control group (3.5%).
In pediatric populations with behavioral disorders, during long-term studies, patients' body weight increased on average by 7.3 kg after 12 months of treatment. The expected annual weight gain for children with normal body weight aged 5–12 years is 3 to 5 kg. Starting at age 12, weight gain remains at 3 to 5 kg per year for girls, while boys gain on average 5 kg per year.
Additional information regarding specific patient categories
Adverse reactions reported more frequently in elderly patients with dementia or in children compared to adults are described below.
Elderly patients with dementia
Transient ischemic attack and cerebrovascular disorders were adverse reactions reported in clinical trials with frequencies of 1.4% and 1.5%, respectively, in elderly patients with dementia. Additionally, the following adverse reactions were reported at a frequency ≥5% in elderly patients with dementia and at least twice as high as in other adult patient groups: urinary tract infections, peripheral edema, lethargy, and cough.
Children
Overall, the expected adverse reactions in children are similar to those in adults in terms of frequency, type, and severity.
Adverse reactions observed in children (aged 5 to 17 years) with a frequency ≥5% and at least twice as high as in adult patients include: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhea, and enuresis.
The long-term impact of risperidone treatment on sexual maturation and growth has not been fully established (see section "Special instructions").
Reporting suspected adverse reactions.
Reporting of suspected adverse reactions after medicine registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life.
2 years.
Storage conditions.
Store at a temperature not exceeding 30 °C. Do not freeze.
Keep out of reach of children.
Packaging.
30 ml or 100 ml in a glass bottle with a tamper-evident closure cap. Each bottle is packaged in a cardboard box together with a 3 ml dosing syringe and a syringe adapter.
30 ml or 100 ml in a glass bottle with a child-resistant closure cap. Each bottle is packaged in a cardboard box together with a 3 ml dosing syringe and a syringe adapter.
Prescription status.
Prescription only.
Manufacturer.
LLC "KUSUM PHARM".
Manufacturer's location and address of business activity.
40020, Ukraine, Sumy region, Sumy city, Skryabina Street, 54.
or
Manufacturer.
LLC "GLEDFARM LTD".
Manufacturer's location and address of business activity.
40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia Street, 54.