Rispetril
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RISPETRIL (RISPETRIL)
Composition:
Active substance: risperidone;
1 ml of solution contains 1 mg of risperidone;
Excipients: purified water, benzoic acid (E 210), tartaric acid, sodium hydroxide, sorbitol solution (E 420).
Pharmaceutical form. Oral solution.
Main physicochemical characteristics: odorless, clear liquid.
Pharmacotherapeutic group. Antipsychotic agents. 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 does not exhibit affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which is related to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser extent compared to classical neuroleptics. The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect to include negative and affective symptoms of schizophrenia.
Pharmacokinetics.
Risperidone is metabolized to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to that of risperidone.
Absorption. After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1–2 hours; in elderly patients, peak concentrations are reached within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). Food does not affect the absorption of the drug; therefore, risperidone can be taken regardless of meals. Absolute bioavailability is 66% in fast metabolizers and 82% in slow metabolizers.
Distribution. Risperidone is rapidly distributed throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and acidic 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 reached within 4–5 days.
Biological transformation and elimination. Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which has 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 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 elimination 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 of the drug (within the therapeutic dose range).
Elderly patients and patients with renal or hepatic impairment. A pharmacokinetic study of single-dose administration in elderly patients demonstrated that such 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 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, 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 revealed no apparent influence of sex, age, or smoking habit on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Clinical characteristics.
Indications.
- For the treatment of schizophrenia;
- for the treatment of moderate to severe manic episodes in bipolar disorder;
- for 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 no response to non-pharmacological treatment approaches (see sections "Dosage and administration" and "Special precautions");
- for symptomatic short-term treatment (up to 6 weeks) of marked aggression associated with behavioral disorders in children from 5 years of age and adolescents with below-average intellectual development or intellectual disability, diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological therapy should be an integral part of a comprehensive treatment program including psychological support and educational interventions. It is recommended that Risperdal be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or a physician experienced in managing 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: parkinsonism, visual hallucinations, gait instability).
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions.
Medicinal products that prolong the QT interval.
Antipsychotics, including risperidone, should be used cautiously in combination 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 (containing quinine, mefloquine), agents causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, and agents that inhibit hepatic metabolism of risperidone. This list is indicative and not exhaustive.
Central-acting agents and alcohol.
Risperidone should be used with caution in combination with other centrally acting substances, particularly alcohol, opioids, antihistamines, and benzodiazepines, due to an increased risk of sedation.
Levodopa and dopamine agonists.
Risperdal may exhibit antagonistic effects toward levodopa and other dopamine agonists. If such a combination is considered essential, particularly 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 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 following dose adjustment of one or both agents (see section "Special precautions").
Paliperidone.
Concomitant use of oral Risperdal with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone, and their combination may result in an additive effect of the active antipsychotic fraction.
Pharmacokinetic interactions.
Food does not affect the absorption of Risperdal.
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, as well as 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 Risperdal with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but to a lesser extent than 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 initiation of concomitant therapy, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the dose of Risperdal.
Inhibitors of CYP3A4 and P-gp.
Concomitant use of Risperdal with potent inhibitors of CYP3A4 and/or P-gp may substantially increase plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation of concomitant therapy, and upon discontinuation of itraconazole or other potent inhibitors of CYP3A4 and/or P-glycoprotein, the physician should review the dose of Risperdal.
Inducers of CYP3A4 and P-gp.
Concomitant use of Risperdal 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 dose of Risperdal. The effect of CYP3A4 inducers is time-dependent: maximum effect may be 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 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 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 Risperdal in children did not affect the pharmacokinetics or efficacy of Risperdal.
Effects of other medicinal products on the pharmacokinetics of risperidone.
Antibacterial medicinal products
- Erythromycin, a moderate inhibitor of CYP3A4 and inhibitor of P-gp, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Rifampicin, a potent inducer of CYP3A4 and inducer of P-gp, reduces plasma concentrations of the active antipsychotic fraction.
Cholinesterase inhibitors
- Donepezil and galantamine, substrates of CYP2D6 and CYP3A4, do not demonstrate clinically significant effects on the pharmacokinetics of risperidone or the active antipsychotic fraction.
Antiepileptic medicinal products
- Carbamazepine, a potent inducer of CYP3A4 and inducer of P-gp, reduces plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may be observed with phenytoin and phenobarbital, which are also inducers of hepatic enzymes CYP3A4 and P-glycoprotein.
- Topiramate moderately reduces the bioavailability of risperidone but does not affect the bioavailability of the active antipsychotic fraction. This interaction is unlikely to cause a clinically significant effect.
Antifungal medicinal products
- Itraconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg 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 plasma concentrations of 9-hydroxyrisperidone.
Antipsychotic medicinal products
- Phenothiazines may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction.
Antiviral medicinal products
- Protease inhibitors: data from studies are lacking; since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and ritonavir-boosted protease inhibitors may increase plasma concentrations of the active antipsychotic fraction of risperidone.
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.
SSRIs [selective serotonin reuptake inhibitors] and tricyclic antidepressants
- Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but to a lesser extent than the active antipsychotic fraction.
- Paroxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but (at doses up to 20 mg daily) to a lesser extent than 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 plasma concentrations of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg daily may increase plasma concentrations of the active antipsychotic fraction of risperidone.
Effects 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.
Elderly 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, based on the results of 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 fatal events 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 indicate that elderly patients with dementia treated with conventional (typical) antipsychotics have a slightly increased risk of death compared to patients who did not receive antipsychotics. Based on available data, the exact level of this risk cannot be determined, and the cause of the increased risk is unknown.
Concomitant use with furosemide.
An increased mortality rate was observed in elderly patients with dementia during a placebo-controlled trial when risperidone was used concomitantly with furosemide (7.3%; mean age: 89 years, range: 75–97 years), compared to patients treated only with risperidone (3.1%; mean age: 84 years, range: 70–96 years) or only with furosemide (4.1%; mean age: 80 years, range: 67–90 years). Increased mortality among patients treated with risperidone and furosemide together 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 explaining this observation have not been established. The cause of death was also 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 initiating treatment. No increased mortality was observed in patients who received risperidone with other diuretics. Dehydration, regardless of treatment, was a common risk factor for death 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 experienced a higher incidence (approximately three times higher) of cerebrovascular adverse events (strokes and transient ischemic attacks), including fatal outcomes, compared to those receiving placebo (mean age: 85 years; range: 73–97 years).
Pooled data from six placebo-controlled trials involving elderly patients with dementia (aged 65 years and older) showed cerebrovascular disorders (serious and non-serious, combined) occurred in 3.3% (33/1009) of patients treated with risperidone, compared to 1.2% (8/712) of placebo-treated patients. 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 with other antipsychotics or in 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, patients with types of dementia other than Alzheimer's dementia should not be treated with risperidone.
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 events, such as sudden weakness, facial, arm, or leg numbness, or speech and vision disturbances. In such cases, 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 in the absence of potential risk of harm to self or others.
Patients should be regularly monitored during treatment, and the need for continued therapy should be periodically reassessed.
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.
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 during the post-marketing period (< 1/10,000 patients).
Patients with a history of significant leukocyte reduction or with 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 appear 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 occur. In cases of severe neutropenia (< 1 × 10⁹/L), risperidone treatment should be discontinued, and leukocyte counts should be monitored until recovery.
Tardive dyskinesia / extrapyramidal symptoms.
Tardive dyskinesia, characterized by involuntary rhythmic movements (predominantly of the tongue and/or face), has been reported with drugs possessing dopamine receptor antagonist properties. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs or symptoms of tardive dyskinesia appear, discontinuation of all antipsychotic medications should be considered.
Caution is advised when using psychostimulants (e.g., methylphenidate) concomitantly with risperidone, as extrapyramidal symptoms may occur when adjusting the dose of either agent. 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. It is characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated creatine phosphokinase levels. Additional features include myoglobinuria (rhabdomyolysis) and acute renal failure. If neuroleptic malignant syndrome develops, all antipsychotic agents, including Risperidone, must 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 heightened sensitivity to antipsychotics (e.g., confusion, reduced pain sensitivity, postural instability with frequent falls, in addition to extrapyramidal symptoms).
Hyperglycemia and diabetes mellitus.
Cases of hyperglycemia, diabetes mellitus, and worsening of pre-existing diabetes have been reported during treatment with risperidone. Some patients previously had excess body weight, which may have been a contributing factor. Diabetic ketoacidosis has been reported very rarely, and diabetic coma has been reported rarely. 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 (such as polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should be regularly assessed 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 experiencing adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, impaired fertility, decreased libido, erectile dysfunction, and 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 association 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 or prolactin-dependent tumors.
QT interval prolongation.
QT interval prolongation has been observed very rarely during the post-marketing period. As with other antipsychotics, risperidone should be used with caution in patients with cardiovascular disorders, a family history of QT prolongation, bradycardia, or electrolyte imbalances (hypokalemia, hypomagnesemia), as these conditions 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 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 under conditions where elevated core body temperature may occur, such as intense physical exercise, exposure to high environmental temperatures, concomitant therapy with anticholinergic agents, or dehydration.
Anti-emetic effect.
In preclinical studies, risperidone demonstrated anti-emetic properties. This effect may mask symptoms of overdose with 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 a reduced ability to eliminate the active antipsychotic fraction of the drug compared to those with normal renal function. In patients with impaired hepatic function, increased plasma concentrations of free risperidone have been 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 potential 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 increases the risk of complications during and after ocular surgery. The ophthalmic surgeon should be informed of current or past antipsychotic use. The potential benefits of discontinuing α1-blocking agents before surgery have not been established— the risks of discontinuing antipsychotic therapy should be weighed.
Children.
The risk-benefit ratio should be carefully considered before prescribing Risperidone to children or adolescents with behavioral disorders, and physical and social causes of aggressive behavior (e.g., pain stimuli or inappropriate environmental response) should be evaluated.
The sedative effect of risperidone should be carefully monitored in pediatric patients due to potential effects on learning ability. Adjusting the time of 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 body weight measurement is recommended before starting treatment, with regular monitoring during therapy. Growth changes in long-term open-label extension studies were within expected age-related norms. The effect of long-term risperidone treatment on sexual maturation and growth has not been adequately studied.
Due to potential effects of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status may be required, including measurements of height, body weight, assessment of sexual maturation, menstrual cycle, and other prolactin-dependent phenomena.
Results from a small post-marketing observational study showed that patients aged 8–16 years receiving risperidone were on average 3.0–4.8 cm taller than those receiving other antipsychotics. However, data from this study are insufficient to determine whether risperidone affects final adult height, whether the measurement results are directly due to risperidone's effect on bone growth, whether the underlying disease influences bone growth, or whether improved disease control leads to greater height gain.
Extrapyramidal symptoms and other movement disorders should be regularly monitored during risperidone treatment.
For dosage recommendations in children, see section "Dosage and administration."
Excipients.
Risperidone oral solution contains benzoic acid (E 210). Increased bilirubin levels may lead to neonatal jaundice, which may progress to kernicterus (deposition of unconjugated bilirubin in brain tissue).
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 antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of developing reversible extrapyramidal symptoms and/or withdrawal syndrome. Symptoms include agitation, unusual increase or decrease in muscle tone, tremor, drowsiness, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be closely monitored.
Risperidone is not recommended during pregnancy except in cases of life necessity. If discontinuation of Risperidone during pregnancy is required, it should not be stopped abruptly.
Breastfeeding.
In animal studies, risperidone and 9-hydroxyrisperidone were excreted in breast milk. Observations suggest that risperidone and 9-hydroxyrisperidone may also be excreted in human breast milk. There are no data on adverse reactions in breastfed infants. Therefore, the benefits of breastfeeding should be weighed against the potential risks to the infant.
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 or operate machinery due to its potential effects on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving or operating machinery until their individual sensitivity to the drug is known.
Method of Administration and Dosage.
Dosage.
Schizophrenia.
Adults.
Risperdal can be taken once or twice daily.
Treatment should be initiated at 2 mg of Risperdal per day; on the second day, the dose may be increased to 4 mg. After that, 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 a reduced initial and maintenance dose.
Doses exceeding 10 mg of risperidone per day have not demonstrated greater efficacy compared to lower doses, but may increase the risk of extrapyramidal symptoms.
The safety of doses above 16 mg 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.
The use of this medicinal product is not recommended in children (under 18 years of age).
Manic episodes in bipolar disorder.
Adults.
The recommended initial dose of Risperdal 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 Risperdal 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 with use in elderly patients is limited, caution is recommended.
Children.
The use of this medicinal product is not recommended in children (under 18 years of age).
Short-term treatment of severe aggression in patients with Alzheimer's type dementia.
The recommended initial dose is 0.25 mg twice daily. If necessary, the dose may be increased by increments of 0.25 mg twice daily, no more frequently than every other day. For most patients, the optimal dose is 0.5 mg twice daily. However, for some patients, an effective dose is 1 mg twice daily.
Risperdal should not be used for longer than 6 weeks in patients with severe aggression due to Alzheimer's disease. As with other forms of symptomatic treatment, the use of Risperdal 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, 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 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 Risperdal should be periodically reviewed and adjusted throughout therapy.
Children under 5 years of age.
The use of this medicinal product is not recommended in children under 5 years of age.
Patients with hepatic and renal impairment.
In patients with impaired renal function, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with impaired hepatic function, plasma concentrations of the free fraction of risperidone are increased.
Regardless of the indication, these patients should be started on half the usual initial and maintenance doses, and dose titration should be slower.
Risperdal should be used with caution in this patient population.
Method of Administration
Risperdal is intended for oral administration. Food intake does not affect the absorption of Risperdal.
At the end of treatment, gradual dose reduction of the medicinal product is recommended. After abrupt discontinuation of high doses of antipsychotic agents, isolated cases of acute withdrawal symptoms have been observed, including nausea, vomiting, sweating, and insomnia (see section "Adverse Reactions"). Psychotic symptoms may also recur; cases of development 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 therapy with other agents during treatment with Risperdal. When switching from depot antipsychotic therapy, treatment with Risperdal should be initiated instead of the next scheduled injection. The need for continuation of current antiparkinsonian therapy should be periodically evaluated.
Administration of Risperdal oral solution
Risperdal oral solution may be mixed with beverages such as water, coffee, orange juice, or low-fat milk. The product is incompatible with Coca-Cola and most types of tea, including black tea.
Opening the bottle and using the dosing pipette:
- to open the bottle, press down on the cap and then turn it counterclockwise;
- insert the pipette into the bottle, then, holding the lower ring of the pipette, pull the upper ring up to the mark corresponding to the required dose of the drug in milliliters (ml or mL) or milligrams (mg or mg);
- while holding the lower ring, remove the pipette from the bottle and dispense its contents into a glass containing 100 mL of beverage (listed above).
The liquid in the glass should be thoroughly mixed before administration.
After use, the dosing pipette should be thoroughly rinsed with water.
Children.
Risperidone is indicated for the treatment of severe aggression in behavioral disorders in children aged 5 years and older.
Overdose.
Symptoms.
Signs and symptoms observed in overdose are the known adverse reactions of the drug, but in an exaggerated form: somnolence and sedation, tachycardia and arterial hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have occurred in overdose. Atrial flutter/fibrillation associated with overdose of Risperdal in combination with paroxetine has been reported.
In cases of acute overdose, consider the possibility that the patient may have ingested multiple medicinal products.
Treatment.
Ensure and maintain a patent airway to provide adequate ventilation and oxygenation. Activated charcoal, possibly with a laxative, may be administered no later than one hour after drug ingestion. Cardiovascular monitoring, including ECG monitoring to detect possible arrhythmias, is indicated. Risperidone has no specific antidote; therefore, appropriate supportive measures should be employed. In cases of acute overdose, potential drug interactions involving multiple agents should be considered. 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 agents should be administered. Continuous medical monitoring 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.
Listed below are adverse reactions reported during clinical trials and in the post-marketing period. The frequency of adverse reactions is categorized as follows: 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 group, 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 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 level |
| Very rare |
diabetic ketoacidosis |
| Psychiatric disorders |
|
| Very common |
insomnia |
| Common |
sleep disorders, agitation, depression, anxiety |
| Uncommon |
mania, confusion, decreased libido, restlessness, night terrors |
| Rare |
catatonia, somnambulism, sleep-related eating disorders, blunted affect, anorgasmia |
| Nervous system disorders |
|
| Very common |
sedation/somnolence, parkinsonism, headache |
| Common |
akathisia, dystonia, dizziness, dyskinesia, tremor |
| Uncommon |
tardive dyskinesia, cerebral ischemia, unresponsiveness to stimuli, 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, eye movement disorders, 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 disorders, QT interval prolongation on electrocardiogram, bradycardia, electrocardiogram abnormalities, palpitations |
| Rare |
sinus arrhythmia |
| Unknown |
postural orthostatic tachycardia syndrome |
| Vascular disorders |
|
| Common |
arterial hypertension |
| Uncommon |
hypotension, orthostatic hypotension, flushing |
| Rare |
pulmonary embolism, venous thrombosis |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening airway patency, wheezing, stridor, dysphonia, respiratory disorders |
| Rare |
sleep apnea syndrome, hyperventilation |
| Gastrointestinal disorders |
|
| Common |
abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache |
| Uncommon |
fecal incontinence, fecaloma, gastroenteritis, dysphagia, abdominal distension |
| Rare |
pancreatitis, gastrointestinal obstruction, tongue edema, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
increased transaminase levels, increased gamma-glutamyl transferase levels, increased 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 |
| Unknown |
Stevens-Johnson syndrome / toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders |
|
| Common |
muscle spasms, musculoskeletal pain, back pain, arthralgia |
| Uncommon |
increased creatine phosphokinase level, posture abnormalities, joint stiffness, joint swelling, muscle weakness, neck pain |
| Rare |
rhabdomyolysis |
| Renal and urinary disorders |
|
| Common |
urinary incontinence |
| Uncommon |
polyuria, urinary retention, dysuria |
| Pregnancy, puerperium and perinatal conditions |
|
| Very rare |
drug withdrawal syndrome in newborns |
| Reproductive system and breast disorders |
|
| Uncommon |
erectile dysfunction, ejaculation disorder, amenorrhea, menstrual cycle disturbance, gynecomastia, galactorrhea, sexual dysfunction, breast pain, vaginal discharge |
| Rare |
priapism, menstrual delay, breast engorgement, breast enlargement, breast discharge |
| General disorders |
|
| Common |
edema, fever, chest pain, asthenia, fatigue, pain |
| Uncommon |
facial swelling, chills, increased body temperature, gait disturbance, thirst, chest discomfort, hot flushes, unusual sensations, discomfort |
| Rare |
hypothermia, decreased body temperature, cold sensation in extremities, drug withdrawal syndrome, induration |
| Injury and poisoning |
|
| Common |
falls |
| Uncommon |
postoperative 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 occurred in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients taking risperidone.
c Not observed in clinical studies 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 rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, and dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, myoclonus), 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 an extrapyramidal origin. Insomnia includes: difficulty falling asleep, intrasomnic disorder. Seizures include generalized tonic-clonic seizure. Menstrual disorders include: irregular menstruation, oligomenorrhea. Edema includes: generalized edema, peripheral edema, pitting edema.
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 Risperdal.
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 use. Other cardiac adverse reactions associated with antipsychotic use that may prolong the QT interval include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and atrial flutter/fibrillation.
Venous thromboembolism
Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported during antipsychotic treatment.
Weight gain
In placebo-controlled trials lasting 6 to 8 weeks, the incidence of weight gain ≥7% was statistically significantly higher in patients receiving risperidone (18%) compared to placebo (9%). In 3-week placebo-controlled trials in adult patients with acute mania, the incidence of weight gain ≥7% was comparable between risperidone (2.5%) and placebo (2.4%) groups, and slightly higher in the active control group (3.5%).
In pediatric populations with behavioral disorders, body weight increased on average by 7.3 kg after 12 months of treatment in long-term studies. The expected annual weight gain in children with normal body weight aged 5–12 years is 3 to 5 kg. From age 12 onward, annual weight gain in girls remains at 3 to 5 kg, while boys gain on average 5 kg per year.
Special 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 occurring during clinical trials at frequencies of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, urinary tract infections, peripheral edema, lethargy, and cough were observed in elderly patients with dementia at frequencies ≥5% and at least twice as high as in other adult patient groups.
Children
Overall, the frequency, type, and severity of expected adverse reactions in children are similar to those in adults.
Adverse reactions observed in children (aged 5 to 17 years) at 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, diarrhea, and enuresis.
The long-term impact of risperidone treatment on sexual maturation and growth has not been fully studied (see section "Special precautions for use").
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, 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: https://aisf.dec.gov.ua.
Shelf life: 2 years.
Storage conditions.
Store at temperatures not exceeding 30 °C, in a place inaccessible to children. Do not freeze.
Packaging.
30 ml in a bottle, 1 bottle with a dosing device in a cardboard box.
Prescription status. Prescription only.
Manufacturer: Pharmascience Inc. /
Pharmascience Inc.
Manufacturer's address and place of business.
6111 Royalmount Avenue, Suite 100, Montreal, Quebec H4P 2T4, Canada /
6111 Royalmount Avenue 100, Montreal, Quebec H4P 2T4, Canada.