Torando
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORNEDO® (TORENDO®)
Composition:
Active ingredient: risperidone;
One film-coated tablet contains 1 mg, 2 mg, 3 mg, or 4 mg of risperidone;
Excipients: celactose (containing monohydrate lactose), microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, sodium lauryl sulfate, magnesium stearate, Opadry 03H28758 white (containing propylene glycol);
Additional ingredients:
film-coated tablets of 2 mg: iron oxide yellow (E 172), iron oxide red (E 172);
film-coated tablets of 3 mg: quinoline yellow (E 104);
film-coated tablets of 4 mg: quinoline yellow (E 104), indigo carmine (E 132).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
film-coated tablets of 1 mg: white, oval, biconvex, film-coated tablets with a score line on one side;
film-coated tablets of 2 mg: orange to light brown colored, oval, biconvex, film-coated tablets with a score line on one side;
film-coated tablets of 3 mg: yellow, oval, biconvex, film-coated tablets with a score line on one side;
film-coated tablets of 4 mg: green, oval, biconvex, film-coated tablets with a score line on one side.
Pharmacotherapeutic group. Antipsychotic agents. Risperidone.
ATC code N05A X08.
Pharmacological Properties
Pharmacodynamics
Risperidone is a selective monoaminergic antagonist with characteristic properties. It has high affinity for both serotonin 5-HT2 receptors and dopamine D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2-receptor antagonist, which accounts for its reduction of positive symptoms of schizophrenia, it less frequently causes motor suppression and catalepsy compared to classical neuroleptics. The balanced central antagonism of serotonin and dopamine may lead to a reduced incidence of extrapyramidal side effects and expanded therapeutic efficacy against 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. The absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). The relative bioavailability after oral administration of risperidone in tablet form is 94% (CV = 10%) compared to the liquid formulation. 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 acidic α1-glycoprotein. Risperidone is 90% bound to plasma proteins, while 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 rapid metabolizers, risperidone is quickly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, the conversion is much 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 administration, 70% of the dose is excreted in urine and 14% in feces. The concentration of risperidone and 9-hydroxyrisperidone in urine accounts for 35–45% of the administered dose. The remainder consists of inactive metabolites. After oral administration in patients with psychosis, the elimination half-life is approximately 3 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, 34 hours.
Linearity
Plasma concentrations of risperidone are proportional to the 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 shown that these patients have a 43% higher concentration of the active antipsychotic fraction, a 38% longer elimination half-life, and a 30% lower clearance of the active antipsychotic fraction.
In adult patients with impaired renal function, the clearance of the active fraction was ~48% of that in adults without renal impairment. In adults with severe renal impairment, clearance was ~31% of that in adults without renal impairment. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (approximately 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in young adults). In patients with hepatic insufficiency, normal plasma concentrations of risperidone were observed, but the mean value of the free fraction of risperidone in plasma was increased by 37.1%.
After oral administration, the clearance and elimination half-life of risperidone and the active antipsychotic fraction in patients with moderate to severe hepatic impairment did not differ significantly from those in young healthy volunteers.
Children
The pharmacokinetics of risperidone, 9-hydroxyrisperidone, and the active antipsychotic fraction in children are similar to those in adults.
Sex, race, and smoking
Population pharmacokinetic analysis did not reveal any significant influence of sex, age, or smoking habits 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");
- short-term symptomatic treatment (up to 6 weeks) of marked aggression in behavioral disorders in children aged 5 years and adolescents with below-average intellectual development or intellectual disability diagnosed according to DSM-IV criteria, where 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 interventions. It is recommended that Torindo® 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 postural parkinsonism).
Dementia and suspected dementia with Lewy bodies (in addition to dementia symptoms, at least two of the following: parkinsonism, visual hallucinations, gait instability).
Interaction with other medicinal products and other types of interactions.
Pharmacodynamic interactions.
Medicinal products that prolong the QT interval.
As with other antipsychotics, caution should be exercised when administering risperidone with medicinal products that prolong the QT interval, such as antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, certain antimalarials (quinine, mefloquine), and products causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or agents that inhibit hepatic metabolism of risperidone. This list is indicative and not exhaustive.
Central-acting agents and alcohol.
Risperidone should be used cautiously in combination with other centrally acting substances, including alcohol, opioids, antihistamines, and benzodiazepines, due to an increased risk of sedation.
Levodopa and dopamine agonists.
Torindo® may exhibit antagonistic effects to levodopa and other dopamine agonists. If such 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 reported during the post-marketing period with concomitant use of risperidone and antihypertensive medicinal products.
Psychostimulants.
Use of risperidone in combination with psychostimulants (e.g., methylphenidate) may lead to the emergence of extrapyramidal symptoms after dose adjustment of one or both agents (see section "Special precautions").
Paliperidone.
Concomitant use of oral Torindo® with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone and their combination may lead to additive effects of the active antipsychotic fraction.
Pharmacokinetic interactions.
Food does not affect the absorption of Torindo®.
Risperidone is mainly 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 Torindo® with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but to a lesser extent 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, as well as upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the dose of Torindo®.
CYP3A4 and P-gp inhibitors.
Concomitant use of Torindo® with potent CYP3A4 and/or P-gp inhibitors may substantially increase plasma concentrations of the active antipsychotic fraction of risperidone. At the start of concomitant use, as well as upon discontinuation of itraconazole or other potent CYP3A4 and/or P-glycoprotein inhibitors, the physician should review the dose of Torindo®.
CYP3A4 and P-gp inducers.
Concomitant use of Torindo® with potent CYP3A4 and/or P-gp inducers may reduce plasma concentrations of the active antipsychotic fraction of risperidone. At the start of therapy, as well as upon discontinuation of carbamazepine or other strong CYP3A4/P-glycoprotein inducers, the physician should review the dose of Torindo®. The effect of CYP3A4 inducers depends on time, with maximum impact achieved at least 2 weeks after initiation of treatment. Accordingly, after discontinuation of the inducer, CYP3A4 induction may persist for at least 2 weeks.
Medicinal products with high 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 for that product regarding metabolic pathways and need for dose adjustment should be consulted.
Children.
Interaction studies have been conducted only in adult patients. It is unknown whether the results obtained can be applied to children.
Concomitant use of psychostimulants (e.g., methylphenidate) with Torindo® in children did not affect the pharmacokinetics or efficacy of Torindo®.
Effect of other medicinal products on the pharmacokinetics of risperidone.
Antibacterial medicinal products
- Erythromycin, a moderate CYP3A4 inhibitor and P-gp inhibitor, does not alter the pharmacokinetics of risperidone or the active antipsychotic fraction.
- Rifampicin, a potent CYP3A4 inducer and P-gp inducer, 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 CYP3A4 inducer and P-gp inducer, 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 risperidone bioavailability 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 CYP3A4 inhibitor and P-gp inhibitor, 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 CYP3A4 inhibitor and P-gp inhibitor, 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: study data are lacking; since ritonavir is a potent CYP3A4 inhibitor and a weak CYP2D6 inhibitor, 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 CYP3A4 inhibitor and P-gp inhibitor, 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 risperidone bioavailability and minimally affect bioavailability of the active antipsychotic fraction.
SSRIs and tricyclic antidepressants
- Fluoxetine, a potent CYP2D6 inhibitor, increases plasma concentrations of risperidone but to a lesser extent than the active antipsychotic fraction.
- Paroxetine, a potent CYP2D6 inhibitor, 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 CYP2D6 inhibitor, and fluvoxamine, a weak CYP3A4 inhibitor, at doses up to 100 mg daily do not cause clinically significant changes in concentrations of the active antipsychotic fraction of risperidone. However, doses of sertraline or fluvoxamine exceeding 100 mg daily may increase 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 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 dehydro-aripiprazole.
Cardiac glycosides
- Risperidone has no clinically significant effect on the pharmacokinetics of digoxin.
Lithium
- Risperidone has no clinically significant effect on the pharmacokinetics of lithium.
Concomitant use of risperidone with furosemide.
See section "Special precautions" regarding increased mortality in elderly patients with dementia when used concomitantly with furosemide.
Special precautions for use.
Geriatric patients with dementia.
Increased mortality.
In a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including Torendo®, a higher mortality rate was observed in elderly patients with dementia treated with atypical antipsychotics compared to placebo. In a placebo-controlled trial using Torendo® 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 increased risk of death compared to patients not receiving antipsychotics. Based on available data, the exact level of this risk cannot be determined, and the cause of 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 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 in patients treated concomitantly with risperidone and furosemide was observed in two out of four clinical trials. No increased mortality was observed in patients who received risperidone concomitantly with other diuretics.
The pathophysiological mechanisms explaining this observation have not been established. The cause of death was not uniform. However, particular caution should be exercised when prescribing this combination, and the risks and benefits of this combination or combinations with other potential diuretics should be carefully evaluated before prescribing. No increased mortality was observed in patients who received risperidone with other diuretics. 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, elderly patients with dementia treated with Torendo® showed a higher incidence (approximately three times) 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) in 3.3% (33/1009) of patients treated with Torendo® compared to 1.2% (8/712) of patients receiving placebo. The ratio between the Torendo® and placebo groups (odds ratio; 95% CI) was 2.96 (1.34; 7.50). The mechanism of this increased risk is unknown. An increased risk of cerebrovascular adverse events cannot be ruled out for other antipsychotics or other patient populations. Torendo® should be used with caution in patients with risk factors for stroke.
The risk of cerebrovascular adverse effects is significantly higher in patients with mixed or vascular dementia compared to Alzheimer's dementia. Therefore, risperidone should not be prescribed to patients with types of dementia other than Alzheimer's dementia.
The risks and benefits of prescribing Torendo® 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, and speech or vision disturbances. All treatment options, including discontinuation of Torendo® therapy, should be promptly considered.
For persistent aggression in patients with moderate to severe Alzheimer's disease, Torendo® 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, especially at the beginning of treatment. During the post-marketing period, clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive agents. Torendo® 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 with antipsychotic drugs, including risperidone. Agranulocytosis has been reported very rarely (<1/10,000 patients) during 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, and risperidone should be discontinued if signs of significant leukocyte reduction occur in the absence of other causes.
Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms develop. In cases of severe neutropenia (<1×10⁹/L), treatment with risperidone 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 developing tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, discontinuation of all antipsychotic drugs 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 drugs. 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 neuroleptic drugs, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated creatine phosphokinase levels. Additional features include myoglobinuria (rhabdomyolysis) and acute renal failure. In case of neuroleptic malignant syndrome, all antipsychotic drugs, including Torendo®, should be discontinued.
Parkinson's disease and dementia with Lewy bodies.
Physicians should carefully consider the risks of using antipsychotic drugs, including Torendo®, 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).
Hypoglycemia and diabetes mellitus.
Cases of hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with Torendo®.
In some cases, prior obesity was reported, which may have been a triggering factor. Very rarely, ketoacidosis and rarely diabetic coma have been reported. Appropriate clinical monitoring according to antipsychotic drug use guidelines is recommended. Patients taking any atypical antipsychotics, including Torendo®, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should be regularly examined for worsening glucose control.
Weight gain.
Significant weight gain has been reported with Torendo® use. Monitoring of body weight is recommended.
Hyperprolactinemia.
Hyperprolactinemia is a common adverse effect of Torendo® treatment. Patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, and galactorrhea) should have their prolactin levels monitored.
In vitro tissue culture studies suggest that prolactin may stimulate the growth of human breast tumor cells. Although a clear association with antipsychotic use has not been established in clinical and epidemiological studies, risperidone should be prescribed with caution in patients with a history of relevant pathology. Torendo® should be used cautiously in patients with hyperprolactinemia and prolactin-dependent tumors.
QT interval prolongation.
QT interval prolongation has been reported very rarely during the post-marketing period. As with other antipsychotics, risperidone should be used with caution in patients with known cardiovascular disorders, a family history of QT interval 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 drugs that prolong the QT interval.
Seizures.
Torendo® 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 Torendo® treatment due to its alpha-adrenergic blocking effect.
Body temperature regulation.
Antipsychotic drugs may impair the body's ability to reduce core body temperature. Appropriate care is recommended for patients receiving Torendo® 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 drugs having anticholinergic activity, or dehydration.
Anti-emetic effect.
In preclinical studies, risperidone demonstrated anti-emetic properties. This property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, or brain tumors.
Liver and kidney 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 liver 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 drugs. 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 Torendo® 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 Torendo®.
IFIS may increase the risk of ocular surgical complications during and after the procedure. The ophthalmic surgeon should be informed of past or current use of antipsychotic drugs. The potential benefits of discontinuing α1-blocking drugs before surgery have not been established; the risk of discontinuing antipsychotic treatment should be carefully weighed.
Children.
Before prescribing Torendo® to children or adolescents with behavioral disorders, the risk-benefit ratio should be carefully evaluated, and physical and social causes of aggressive behavior, such as pain stimuli or inappropriate response to the environment, should be assessed.
The sedative effect of risperidone should be carefully monitored in pediatric patients due to potential consequences for learning ability. Adjusting the time of risperidone administration may improve the impact of sedation on children's and adolescents' attention.
Risperidone use is associated with slight increases in body weight and body mass index (BMI). Initial body weight measurement before starting treatment and regular monitoring during treatment are recommended. Growth changes in long-term open-label extension studies were within expected age-related norms. The long-term effect of 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. The data from this study are insufficient to determine whether risperidone affects final adult height, whether the measurement results directly depend on 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 growth.
During risperidone treatment, extrapyramidal symptoms and other movement disorders should be regularly monitored.
For dosage recommendations in children, see section "Dosage and administration".
Excipients.
Torendo® film-coated tablets contain lactose; therefore, patients with hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medication.
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. These symptoms include agitation, unusual muscle tone (increased or decreased), tremor, drowsiness, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be closely monitored.
Torendo® is not recommended during pregnancy except in cases of life necessity. If discontinuation of Torendo® treatment during pregnancy is required, it should not be done 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 child should be carefully weighed.
Fertility
Like other medicinal products that are dopamine D2 receptor antagonists, Torendo® 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 affect reaction speed when driving or operating machinery.
Torendo® may have a minor 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.
Administration and Dosage
Torendo® can be administered once or twice daily. Doses exceeding 8 mg should be divided into two administrations (morning and evening).
For achieving doses of 0.25–2.5 mg, risperidone in the form of oral solution is recommended.
Dosage
Schizophrenia
Adults
Torendo® may be administered once or twice daily.
Treatment should be initiated at a dose of 2 mg Torendo® 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 higher efficacy compared to lower doses but may cause extrapyramidal symptoms.
The safety of doses exceeding 16 mg per day has not been studied.
Elderly patients (aged 65 years and older)
The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily.
Children
The use of the drug is not recommended in children (under 18 years of age).
Manic episodes in bipolar disorders
Adults
The recommended initial dose of Torendo® is 2 mg once daily. The dose may be individually increased by 1 mg/day, no more frequently than every 24 hours. The recommended dose range is 1–6 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 Torendo® 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. Due to limited experience with use in elderly patients, caution is recommended.
Children
The use of the drug is not recommended in children (under 18 years of age).
Short-term treatment of marked aggression in patients with Alzheimer's type dementia
The recommended initial dose is 0.25 mg twice daily. Risperidone oral solution is the recommended dosage form for the 0.25 mg dose. 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.
Torendo® should not be used for longer than 6 weeks in patients with marked aggression due to Alzheimer's disease. As with other forms of symptomatic treatment, the use of Torendo® should be periodically reviewed and adjusted throughout therapy.
Short-term symptomatic treatment (up to 6 weeks) of marked aggression in behavioral disorders
Children and adolescents aged 5 to 18 years
Patients with body weight ≥ 50 kg
The recommended initial dose is 0.5 mg once daily. If necessary, the dose should be adjusted by increasing by 0.5 mg once daily, no more frequently than every other day. The optimal dose for most patients is 1 mg once daily. However, for some patients, no more than 0.5 mg once daily may be sufficient to achieve a positive effect, whereas others may require 1.5 mg once daily.
Patients with body weight < 50 kg
The recommended initial dose is 0.25 mg once daily. Risperidone oral solution is the recommended dosage form for the 0.25 mg dose. If necessary, the dose may be adjusted by increasing by 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, whereas others may require 0.75 mg once daily.
As with other forms of symptomatic treatment, the use of Torendo® should be periodically reviewed and adjusted throughout therapy.
Children
The use of the drug is not recommended in children under 5 years of age.
Patients with hepatic and renal impairment.
In patients with renal impairment, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with hepatic impairment, the concentration of free risperidone fraction in plasma is increased.
Regardless of the indication, these patients should receive half the initial and maintenance doses; dose titration should be slower.
Torendo® should be used with caution in this patient population.
Administration
Torendo® is intended for oral administration. Food intake does not affect the absorption of Torendo®.
At the end of treatment, gradual discontinuation of the drug is recommended. After abrupt discontinuation of high doses of antipsychotics, isolated cases of acute withdrawal symptoms have been observed, including nausea, vomiting, sweating, and insomnia (see section "Adverse Reactions"). Psychotic symptoms may also recur, and cases of involuntary movements (e.g., akathisia, dystonia, and dyskinesia) have been reported.
Switching from therapy with other antipsychotics.
If clinically justified, it is recommended to gradually discontinue previous antipsychotic therapy when initiating Torendo®. When switching from depot antipsychotic formulations, treatment with Torendo® should be initiated instead of the next scheduled injection. The need for continuing current antiparkinsonian therapy should be periodically evaluated.
Children
Risperidone is used to treat marked aggression in 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, manifested in an intensified form: somnolence and sedation, tachycardia and arterial hypotension, as well as extrapyramidal symptoms. QT interval prolongation and seizures have been reported. Atrial fibrillation/flutter associated with overdose of Torendo® in combination with paroxetine has been reported.
In cases of acute overdose, the possibility of ingestion of multiple drugs should be considered.
Treatment.
Ensure and maintain a patent airway to provide adequate ventilation and oxygenation. Administration of activated charcoal with a laxative should be considered within one hour of drug ingestion. Cardiovascular monitoring, including continuous ECG recording to detect possible arrhythmias, is indicated. Risperidone has no specific antidote; therefore, appropriate supportive measures should be implemented. In cases of acute overdose, the possibility of drug interactions involving multiple agents should be analyzed. 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 full recovery of the patient.
Adverse Reactions
The most commonly reported adverse reactions (incidence ≥ 10%) are parkinsonism, sedation/somnolence, headache, and insomnia. Parkinsonism and akathisia are dose-dependent adverse reactions.
The adverse reactions listed below are those reported during clinical trials and in the post-marketing period. Frequency of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and not known (frequency cannot be estimated from the available data).
Within each category, adverse reactions are listed in order of decreasing 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 leukocyte count, thrombocytopenia, anemia, decreased hematocrit, increased eosinophil count |
| Rare |
agranulocytosis |
| Immune system disorders |
|
| Uncommon |
hypersensitivity |
| Rare |
anaphylactic reaction |
| Endocrine system disorders |
|
| Common |
hyperprolactinemia |
| Rare |
disorders of antidiuretic hormone secretion, presence of glucose in urine |
| Metabolism and nutrition disorders |
|
| Common |
weight gain, increased appetite, decreased appetite |
| Uncommon |
diabetes mellitus, hyperglycemia, polydipsia, weight loss, anorexia, increased cholesterol level |
| Rare |
water intoxication, hypoglycemia, hyperinsulinemia, 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, sleepwalking, sleep-related eating disorder, blunted affect, anorgasmia |
| Nervous system disorders |
|
| Very common |
sedation/somnolence, parkinsonism, headache |
| Common |
akathisia, dystonia, dizziness, dyskinesia, tremor |
| Uncommon |
late dyskinesia, cerebral ischemia, unresponsiveness to stimuli, loss of consciousness, depressed level of consciousness, seizures, syncope, psychomotor hyperactivity, balance disorders, coordination impairment, postural dizziness, attention disturbance, 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 |
| Vascular disorders |
|
| Common |
arterial hypertension |
| Uncommon |
hypotension, orthostatic hypotension, flushing |
| Rare |
pulmonary embolism, venous thrombosis |
| Respiratory system disorders |
|
| Common |
dyspnea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion |
| Uncommon |
aspiration pneumonia, pulmonary congestion, worsening airway patency, wheezing, stridor, dysphonia, respiratory disturbances |
| Rare |
sleep apnea syndrome, hyperventilation |
| Gastrointestinal system disorders |
|
| Common |
abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhea, dyspepsia, dry mouth, toothache |
| Uncommon |
fecal incontinence, fecaloma, gastroenteritis, dysphagia, abdominal distension |
| Rare |
pancreatitis, gastrointestinal tract obstruction, tongue swelling, cheilitis |
| Very rare |
intestinal obstruction |
| Hepatobiliary disorders |
|
| Uncommon |
increased 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 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 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 irregularities, 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 |
post-surgical pain |
a Hyperprolactinemia in some cases may lead to gynecomastia, menstrual disorders, amenorrhea, anovulation, galactorrhea, impaired fertility, decreased libido, erectile dysfunction.
b During placebo-controlled studies, diabetes mellitus was reported in 0.18% of patients receiving risperidone, compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% in patients treated with risperidone.
c Not observed in clinical studies of Torendo®, but 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 muscle rigidity, muscle rigidity, parkinsonian gait, impaired glabellar reflex, parkinsonian tremor), akathisia (akathisia, restlessness, hyperkinesia, restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, myoclonus), 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, intrasomniac 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 an active metabolite of risperidone; therefore, the adverse reaction profiles of these substances (including oral and injectable formulations) are similar. In addition to the adverse reactions listed above, postural orthostatic tachycardia syndrome has been reported with paliperidone use, which may also occur during Torendo® use.
Cardiac disorders: postural orthostatic tachycardia syndrome.
Adverse reactions typical of antipsychotic medicinal products
QT interval prolongation
As with other antipsychotics, QT interval prolongation has been reported during post-marketing use of risperidone. Other cardiac adverse reactions associated with QT prolongation have also been reported with antipsychotic drugs, such as ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and 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 Torendo® versus placebo showing ≥7% body weight gain in placebo-controlled trials lasting 6 to 8 weeks revealed a statistically significant difference in the frequency of weight gain in the Torendo® group (18%) compared to the placebo group (9%). In 3-week placebo-controlled trials in adult patients with acute mania, the incidence of ≥7% body weight gain was comparable between the Torendo® group (2.5%) and the placebo group (2.4%), and slightly higher in the active control group (3.5%).
In pediatric populations with behavioral disorders, during long-term studies, patients' body weight increased on average by 7.3 kg after 12 months of treatment. The expected annual weight gain for children with normal body weight aged 5–12 years is 3 to 5 kg. Starting at age 12, annual weight gain remains at 3 to 5 kg for girls, while boys gain on average 5 kg per year.
Additional information regarding 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 reported in clinical trials with an incidence of 1.4% and 1.5%, respectively, in elderly patients with dementia. Additionally, the following adverse reactions were reported with an incidence ≥5% in elderly patients with dementia and at least twice as high as in other adult patient groups: urinary tract infections, peripheral edema, lethargy, and cough.
Children
Overall, the expected adverse reactions in children are similar to those in adults in terms of frequency, type, and severity.
Adverse reactions observed in children (aged 5 to 17 years) with an incidence ≥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 established (see section "Special precautions").
Reporting suspected adverse reactions
Reporting of adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 5 years.
Storage conditions.
Store at temperatures not exceeding 30°C. Keep out of reach of children.
Packaging.
10 tablets per blister; 2, 3, or 6 blisters per cardboard package.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia /
KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and place of business.
Šmarješka cesta 6, 8501 Novo mesto, Slovenia /
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.