Rispaxol
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RISPAXOL® (RISPAXOL)
Composition:
Active substance: risperidone;
One tablet contains 2 mg or 4 mg of risperidone;
Excipients: anhydrous lactose, maize starch, magnesium stearate, colloidal anhydrous silicon dioxide, microcrystalline cellulose;
Coating:
2 mg tablets – Opadry Orange OY-8729 (hypromellose, polyethylene glycol 400, titanium dioxide (E 171), sunset yellow FCF (E 110), quinoline yellow (E 104)), polyethylene glycol 6000, carnauba wax;
4 mg tablets – Opadry AMB Green 80W21165 (iron oxide (E 172), indigo carmine (E 132), soy lecithin, polyvinyl alcohol, quinoline yellow (E 104), talc, titanium dioxide (E 171), xanthan gum), carnauba wax.
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
2 mg tablets – round, biconvex tablets with a score on one side, coated with an orange film. White at the break;
4 mg tablets – round, biconvex tablets with a cross-score on one side, coated with a green film. White at the break.
Pharmacotherapeutic group.
Antipsychotic agents. ATC code N05AX08.
Pharmacological Properties
Pharmacodynamics
Risperidone is a selective monoaminergic antagonist with unique properties. It exhibits high affinity for serotonin 5-HT2 and dopamine D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone shows no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against the positive symptoms of schizophrenia, it does not cause significant motor suppression and induces catalepsy to a lesser degree 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
Absorption
After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1 to 2 hours; in elderly patients, peak concentrations occur within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). Relative bioavailability after oral administration of risperidone in tablet form is 94% (CV = 10%) compared to administration as a solution. Food does not affect drug absorption; therefore, risperidone can be administered independently of food intake. Absolute bioavailability is 66% in rapid metabolizers and 82% in slow metabolizers.
Distribution
Risperidone is rapidly distributed throughout the body. The volume of distribution is 1–2 L/kg. In plasma, risperidone binds to albumin and acid α1-glycoprotein. Risperidone is 90% protein-bound in plasma, while 9-hydroxyrisperidone is 77% protein-bound. Steady-state concentrations of risperidone in the body are achieved within 1 day in most patients. Steady-state concentrations of 9-hydroxyrisperidone are achieved within 4–5 days.
Metabolism and Elimination
Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which has a similar pharmacological activity. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction. The cytochrome CYP2D6 is subject to genetic polymorphism. In rapid metabolizers, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, the metabolism of risperidone is significantly slower. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in rapid metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both rapid and slow metabolizers of cytochrome CYP2D6. Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. 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 of risperidone is approximately 3 hours. The elimination half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, it extends to 34 hours.
Linearity
Plasma concentrations of risperidone are proportional to the administered dose (within the therapeutic dose range).
Elderly patients and patients with renal or hepatic impairment
Pharmacokinetic studies following single-dose administration in elderly patients have 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, 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, plasma concentrations of risperidone were within normal ranges, 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 revealed no apparent influence of sex, age, or smoking habit 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 threat of harm to self or others and when there is no response to non-pharmacological treatment methods (see sections "Dosage and administration" and "Special precautions");
- symptomatic short-term treatment (up to 6 weeks) of marked aggression in behavioral disorders in children from 5 years of age and adolescents with below-average intellectual development or intellectual disability diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other destructive behavior requires pharmacological treatment. Pharmacological treatment should be an integral part of a comprehensive treatment program including psychological support and educational measures. It is recommended that Risperdal® be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or a physician experienced in treating behavioral disorders in children and adolescents.
Contraindications.
Hypersensitivity to the active ingredient or to any excipient of the medicinal product.
Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances).
Dementia and suspected dementia with Lewy bodies (in addition to dementia symptoms, at least two of the following: parkinsonism, visual hallucinations, gait 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 with caution 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.
Clinically significant hypotension has been observed in the post-marketing period during 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 risperidone with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone and their combination may lead to an additive effect of the active antipsychotic fraction.
Pharmacokinetic interactions.
Food does not affect the absorption of risperidone.
Risperidone is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity or potent inhibitors or inducers of CYP3A4 and/or P-gp activity may affect the pharmacokinetics of the active antipsychotic fraction of risperidone.
Potent CYP2D6 inhibitors.
Concomitant use of risperidone with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but less so than the concentration of the active antipsychotic fraction. Higher doses of a potent CYP2D6 inhibitor may increase the concentration of the active antipsychotic fraction of risperidone (e.g., paroxetine, see below). Other CYP2D6 inhibitors such as quinidine are expected to affect plasma concentrations of risperidone similarly. At the start of concomitant use, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the risperidone dose.
Inhibitors of CYP3A4 and P-gp.
Concomitant use of risperidone with potent inhibitors of CYP3A4 and/or P-gp may substantially increase plasma concentrations of the active antipsychotic fraction of risperidone. At the beginning of concomitant use, and upon discontinuation of itraconazole or other potent CYP3A4 and/or P-glycoprotein inhibitors, the physician should review the risperidone dose.
Inducers of CYP3A4 and P-gp.
Concomitant use of risperidone with potent inducers of CYP3A4 and/or P-gp may reduce plasma concentrations of the active antipsychotic fraction of risperidone. At the start of therapy, and upon discontinuation of carbamazepine or other strong inducers of CYP3A4/P-glycoprotein, the physician should review the risperidone dose. The effect of CYP3A4 inducers depends on duration, with maximum impact potentially reached at least two weeks after initiation of treatment. Accordingly, after cessation of use, CYP3A4 induction may persist for at least two weeks.
Medicinal products with high protein binding.
When risperidone is used together with other medicinal products that are highly bound to plasma proteins, clinically significant displacement of either product 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 the 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 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, 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-glycoprotein.
- Topiramate moderately reduces the bioavailability of risperidone and does not affect the bioavailability of the active antipsychotic fraction. It is unlikely that this interaction may cause a clinically significant effect.
Antifungal medicinal products
- Itraconazole, a potent inhibitor of CYP3A4 and inhibitor of P-gp, at a dose of 200 mg daily increases plasma concentrations of the active antipsychotic fraction by approximately 70% when co-administered 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 medicinal products
- Phenothiazines may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction.
Antiviral medicinal products
- Protease inhibitors: study data are lacking; since ritonavir is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and protease inhibitors boosted with ritonavir may increase plasma concentrations of the active antipsychotic fraction of risperidone.
Beta-blockers
- Some beta-blockers may increase plasma concentrations of risperidone, but do not affect plasma concentrations of the active antipsychotic fraction.
Calcium channel blockers
- Verapamil, a moderate inhibitor of CYP3A4 and inhibitor of P-gp, increases plasma concentrations of risperidone and the active antipsychotic fraction.
Medicinal products for gastrointestinal disorders
- H2-receptor antagonists: cimetidine and ranitidine, weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone and minimally affect the bioavailability of the active antipsychotic fraction.
SSRIs and tricyclic antidepressants
- Fluoxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but less so than the concentration of the active antipsychotic fraction.
- Paroxetine, a potent inhibitor of CYP2D6, increases plasma concentrations of risperidone, but (at doses up to 20 mg daily) less so than the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction.
- Tricyclic antidepressants may increase plasma concentrations of risperidone, but not of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at doses up to 100 mg daily do not cause clinically important 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.
Effect of risperidone on the pharmacokinetics of other medicinal products.
Antiepileptic medicinal products
- Risperidone has no clinically important 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 and its active metabolite dehydroaripiprazole.
Cardiac glycosides
- Risperidone has no clinically important effect on the pharmacokinetics of digoxin.
Lithium
- Risperidone has no clinically important 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 rate.
An increased mortality rate has been observed in elderly patients with dementia treated with atypical antipsychotic drugs compared to placebo-treated patients in a meta-analysis of 17 controlled trials of atypical antipsychotics, including risperidone. In a placebo-controlled trial using risperidone in this patient population, the incidence of 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) antipsychotics have a slightly higher 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 in 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.
No pathophysiological mechanisms have been established to explain this observation. The cause of death was not uniform. However, particular caution should be exercised when prescribing this combination, and a careful assessment of risks and benefits of this combination or combinations with other potential diuretics should be performed before prescribing. Dehydration, regardless of treatment, was a common risk factor for mortality and should be carefully monitored in patients with dementia.
Cerebrovascular adverse reactions.
In placebo-controlled clinical trials in patients with dementia treated with risperidone, a higher incidence (approximately three times higher) of cerebrovascular adverse events (including strokes and transient ischemic attacks), some fatal, was observed compared to placebo (mean age: 85 years; range: 73–97 years).
Pooled data from six placebo-controlled trials involving elderly patients with dementia (aged 65 years and older) showed cerebrovascular disorders (serious and non-serious, combined) 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 cerebrovascular adverse events cannot be ruled out for other antipsychotics or other patient populations. Risperidone should be used with caution in patients with risk factors for stroke.
The risk of cerebrovascular adverse events is significantly higher in patients with mixed or vascular dementia compared to Alzheimer’s dementia. Therefore, risperidone should not be prescribed to patients with types of dementia other than Alzheimer’s dementia.
All risks and benefits of prescribing risperidone to elderly patients with dementia, particularly the risk of stroke, should be carefully weighed. Patients and caregivers should be instructed to immediately report signs of possible cerebrovascular events, such as sudden weakness, facial, arm, or leg numbness, speech disturbances, or visual disturbances. All 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, provided there is no potential risk of harm to self or others.
During treatment, patients should be regularly evaluated, and the need for continued therapy should be 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 post-marketing use 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 antipsychotics, including risperidone. Agranulocytosis has been observed very rarely (<1/10,000 patients) in the post-marketing period.
Patients with a history of significant leukocyte reduction or drug-induced leukopenia/neutropenia should be closely monitored during the first few months of treatment. Risperidone should be discontinued if signs of significant leukocyte reduction occur and no other causes are identified.
Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. Risperidone treatment should be discontinued in cases of severe neutropenia (<1×10⁹/L), and leukocyte counts should be monitored until recovery.
Tardive dyskinesia/extrapyramidal symptoms.
Tardive dyskinesia, characterized by involuntary rhythmic movements (mainly of the tongue and/or face), has been reported with drugs having 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 antipsychotics 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 or both agents. Gradual discontinuation of psychostimulants 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 neuroleptics, 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 antipsychotics, including risperidone, should be discontinued.
Parkinson’s disease and dementia with Lewy bodies.
Physicians should consider the risks of using antipsychotics, 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 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 risperidone treatment.
In some cases, prior excessive body weight, which could be a triggering factor, was reported. Very rarely, ketoacidosis and rarely diabetic coma have been reported. Appropriate clinical monitoring according to antipsychotic use guidelines is recommended. Patients taking any atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, weakness), and diabetic patients should be regularly evaluated for worsening glucose control.
Weight gain.
Significant weight gain has been reported during risperidone treatment. Body weight monitoring is recommended.
Hyperprolactinemia.
Hyperprolactinemia is a common adverse effect during risperidone treatment. Monitoring of plasma prolactin levels is recommended in patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, galactorrhea).
In vitro tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although a clear clinical and epidemiological link with antipsychotic use has not been established, risperidone should be prescribed with caution in patients with relevant medical history. Risperidone should be used cautiously in patients with hyperprolactinemia and prolactin-dependent tumors.
QT interval prolongation.
QT interval prolongation has been observed very rarely in the post-marketing period. As with other antipsychotics, 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 medicinal products 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 can cause elevated core body temperature, such as intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic agents, or dehydration.
Antiemetic effect.
In preclinical studies, risperidone demonstrated antiemetic properties. 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 concentrations of the free fraction of risperidone are observed (see section "Dosage and administration").
Venous thromboembolism.
Cases of venous thromboembolism have been reported with antipsychotic medicinal products. 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 the procedure. Ophthalmic surgeons should be informed about current or past use of antipsychotics. The potential benefits of discontinuing α1-blocking agents before surgery have not been established; the risks of discontinuing antipsychotic treatment 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 response to environment) 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 slight increases in body weight and body mass index (BMI). Baseline body weight measurement before treatment initiation and regular 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 impact of prolonged hyperprolactinemia on growth and sexual maturation in children and adolescents, regular clinical monitoring of endocrine status, including height, body 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 antipsychotics. However, the data from this study 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 this is a result of better disease control leading to greater height attainment.
Extrapyramidal symptoms and other movement disorders should be regularly monitored during risperidone treatment.
For dosage recommendations in children, see section "Dosage and administration."
Excipients.
Patients with increased sensitivity to lactose should consider the lactose content (145 mg in each tablet containing 2 mg risperidone; 290 mg in each tablet containing 4 mg risperidone). This medicinal product is contraindicated in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Rispaxol® tablets, film-coated, should be used with caution in patients with hypersensitivity to azo dyes (e.g., sunset yellow FCF (E 110)) due to the possibility of allergic reactions.
Use during pregnancy or breastfeeding.
Pregnancy.
Controlled studies in pregnant women have not been conducted. 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. These symptoms include agitation, unusual muscle tone (increased or decreased), tremor, somnolence, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be carefully monitored.
Rispaxol® is not recommended during pregnancy except in cases of life necessity. If discontinuation of Rispaxol® during pregnancy is necessary, 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 and the potential risks to the infant should be carefully weighed.
Fertility.
Like other medicinal products that are dopamine D2 receptor antagonists, Rispaxol® 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.
Rispaxol® may have a minor or moderate influence 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 medicinal product is known.
Method of Administration and Dosage.
To achieve a dosage of 1 mg, the tablet should be divided in half.
Dosage
Schizophrenia
Adults
Rispolol® may be administered once or twice daily.
Treatment should be initiated at 2 mg of Rispolol® per day. On the second day, the dose may be increased to 4 mg. Thereafter, the dose may be maintained unchanged or, if necessary, further individual dose adjustments may be made.
The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or lower initial and maintenance doses.
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 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
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 Rispolol® is 2 mg once daily. The dose may be individually increased by 1 mg/day at intervals of no less than 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 the course of therapy.
Elderly patients (aged 65 years and older)
The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily. Due to limited experience in elderly patients, caution is recommended when administering the drug.
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, in some patients, an effective dose may be 1 mg twice daily.
Rispolol® 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 Rispolol® should be periodically reviewed and adjusted throughout the course of 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, some patients may achieve a positive effect with no more than 0.5 mg once daily, while others may require 1.5 mg once daily.
Patients with body weight < 50 kg
The recommended initial dose is 0.25 mg once daily. If necessary, the dose may be adjusted by increments of 0.25 mg once daily, no more frequently than every other day. The optimal dose for most patients is 0.5 mg once daily. However, some patients may achieve a positive effect with no more than 0.25 mg once daily, while others may require 0.75 mg once daily.
As with other forms of symptomatic treatment, the use of risperidone should be periodically reviewed and adjusted throughout the course of therapy.
Children
The use of this medicinal product is not recommended in children under 5 years of age.
Patients with Hepatic or 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, the concentration of free risperidone in plasma is increased.
Regardless of the indication, these patients should receive half the standard initial and maintenance doses, and dose titration should be performed more slowly.
Risperidone should be used with caution in this patient population.
Method of Administration
Rispolol® is intended for oral administration. Food intake does not affect the absorption of Rispolol®.
At the end of treatment, gradual discontinuation of the medicinal product 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 (such as akathisia, dystonia, and dyskinesia) have been reported.
Switching from Therapy with Other Antipsychotic Medications.
If clinically justified, it is recommended to gradually discontinue previous antipsychotic therapy when initiating treatment with Rispolol®. When switching from depot antipsychotic formulations, treatment with risperidone should be initiated instead of the next scheduled depot dose. The need for continued use of anti-Parkinson medications should be periodically evaluated.
Children
Risperidone is used to treat severe aggression associated with behavioral disorders in children aged 5 years and older.
Overdose
Symptoms.
Signs and symptoms observed in overdose are the known adverse reactions to the drug, but in an intensified form: somnolence and sedation, tachycardia and arterial hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported in cases of overdose. Atrial flutter associated with overdose of Rispolol® in combination with paroxetine has also been reported.
In cases of acute overdose, the possibility of co-ingestion of multiple medicinal products should be considered.
Treatment.
Ensure and maintain a patent airway to provide adequate ventilation and oxygenation. Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal with a laxative should be considered, if performed within 1 hour of drug ingestion. Cardiovascular monitoring, including continuous ECG recording to detect possible arrhythmias, is indicated.
Risperidone has no specific antidote. Therefore, appropriate supportive measures should be applied. Hypotension and vascular collapse should be managed with intravenous fluids and/or sympathomimetic agents. In the event of acute extrapyramidal symptoms, anticholinergic medications should be administered. Continuous medical observation and monitoring should be maintained until all signs of overdose have completely resolved.
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 eosinophils |
| 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 levels |
| Rare |
water intoxication, hypoglycemia, hyperinsulinemia, increased blood triglycerides |
| 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, sleepwalking, sleep-related eating disorder, blunted affect, anorgasmia |
| Nervous system disorders |
|
| Very common |
sedation/somnolence, parkinsonism, headache |
| Common |
akathisia, dystonia, dizziness, dyskinesia, tremor |
| Uncommon |
tardive 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 rocking |
| Eye disorders |
|
| Common |
blurred vision, conjunctivitis |
| Uncommon |
photophobia, dry eyes, increased lacrimation, eye redness |
| Rare |
glaucoma, impaired eye movement, rotatory nystagmus, eyelid crusting, intraoperative floppy iris syndrome |
| Ear and labyrinth disorders |
|
| Uncommon |
vertigo, tinnitus, ear pain |
| Cardiac disorders |
|
| Common |
tachycardia |
| Uncommon |
atrial fibrillation, atrioventricular block, cardiac conduction disorders, QT interval prolongation on electrocardiogram, bradycardia, electrocardiogram abnormalities, palpitations |
| Rare |
sinus arrhythmia |
| 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 swelling, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
increased transaminases, increased gamma-glutamyl transferase, increased liver enzymes |
| Rare |
jaundice |
| Skin and subcutaneous tissue disorders |
|
| Common |
rash, erythema |
| Uncommon |
urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discoloration, acne, seborrheic dermatitis, skin disorders, skin injury |
| Rare |
drug rash, 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 |
increased creatine phosphokinase, abnormal posture, joint stiffness, joint swelling, muscle weakness, neck pain |
| Rare |
rhabdomyolysis |
| Renal and urinary disorders |
|
| Common |
urinary incontinence |
| Uncommon |
polyuria, urinary retention, dysuria |
| Pregnancy, puerperium and perinatal conditions |
|
| Very rare |
drug withdrawal syndrome in newborns |
| Reproductive system and breast disorders |
|
| Uncommon |
erectile dysfunction, ejaculation disorder, amenorrhea, menstrual cycle disorder, 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 feelings, discomfort |
| Rare |
hypothermia, decreased body temperature, cold sensation in extremities, drug withdrawal syndrome, induration |
| Injury, poisoning and procedural complications |
|
| 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 trials, diabetes mellitus was reported in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients taking risperidone.
c Not observed in clinical studies of risperidone; however, identified during post-marketing surveillance.
d Extrapyramidal disorders include: parkinsonism (hypersalivation, muscle rigidity, parkinsonism, drooling, cogwheel phenomenon, bradykinesia, hypokinesia, mask-like face, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, myoclonus), and dystonia.
Dystonia includes dystonia, hypertonia, torticollis, involuntary muscle contractions, myogenic contractures, blepharospasm, eye movement disorders, tongue paralysis, tic (in the facial area), laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, tongue spasm, trismus. A broader list of symptoms is included, not necessarily of extrapyramidal origin. Insomnia includes difficulty falling asleep, intrasomnic disturbance. Seizures include generalized tonic-clonic seizures. 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 occur with risperidone.
Adverse reactions associated with 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 QT prolongation have also been reported with antipsychotic use, including 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
Comparison of the number of patients treated with risperidone versus placebo who experienced a body weight increase of 7% or more in placebo-controlled trials lasting 6 to 8 weeks showed a statistically significant higher incidence 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 similar between the risperidone group (2.5%) and placebo group (2.4%), 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 remains at 3–5 kg for girls, while boys gain on average 5 kg per year.
Additional information regarding specific patient populations
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. Other adverse reactions reported in elderly patients with dementia at a frequency ≥5% and at least twice that observed in other adult patient groups include: 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 that 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 effects of risperidone treatment on sexual maturation and growth have not been fully studied (see section "Special precautions").
Excipients content
Tablets with a strength of 2 mg contain the colorant Sunset Yellow FC40 (E110), which may cause allergic reactions.
Shelf life. 4 years.
Do not use after the expiry date stated on the packaging.
Storage conditions.
Store in a light-protected place at a temperature not exceeding 25°C.
Keep out of reach of children.
Packaging.
10 tablets in a blister; 2 or 6 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
JSC "Grindeks".
Manufacturer's address and place of business.
53 Krustpils Street, Riga, LV-1057, Latvia.
Tel./fax: +371 67083205 / +371 67083505
E-mail: [email protected]