Rileptid®

INSTRUCTION for medical use of the medicinal product RILEPTID® (RILEPTID®)

Composition:

Active substance: 1 tablet contains risperidone 1 mg or 2 mg or 3 mg or 4 mg;

Excipients: lactose monohydrate, maize starch, microcrystalline cellulose, magnesium stearate, anhydrous colloidal silicon dioxide, sodium lauryl sulfate;

Coating composition:

1 mg tablets: hypromellose, titanium dioxide (E 171), polyethylene glycol 400;

2 mg tablets: Opadry 03B220015 (hypromellose, titanium dioxide (E 171), polyethylene glycol 400, quinoline yellow (E 104));

3 mg and 4 mg tablets: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, indigo carmine (E 132), quinoline yellow (E 104).

Pharmaceutical form. Coated tablets.

Main physicochemical properties:

1 mg tablets – white or almost white, elongated, biconvex coated tablets, engraved with "751" and a stylized letter "E" on one side and a line on the other, odorless or almost odorless;

2 mg tablets – yellow, elongated, biconvex coated tablets, engraved with "752" and a stylized letter "E" on one side and a line on the other, odorless or almost odorless;

3 mg tablets – light green, elongated, biconvex coated tablets, engraved with "753" and a stylized letter "E" on one side and a line on the other, odorless or almost odorless;

4 mg tablets – green, elongated, biconvex coated tablets, engraved with "754" and a stylized letter "E" on one side and a line on the other, odorless or almost odorless.

Pharmacotherapeutic group. Antipsychotics. ATC code N05AX08.

Pharmacological properties.

Pharmacodynamics.

Risperidone is a selective monoaminergic antagonist with unique properties. It exhibits high affinity for serotonergic 5-HT2 and dopaminergic D2 receptors. Risperidone also binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors. Risperidone does not exhibit affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which contributes to its efficacy against the positive symptoms of schizophrenia, it does not cause significant suppression of motor activity and induces catalepsy to a lesser extent compared to classical neuroleptics.

The balanced central antagonism towards serotonin and dopamine reduces the propensity for extrapyramidal side effects and broadens the therapeutic effect to include negative and affective symptoms of schizophrenia.

Pharmacokinetics.

Risperidone in the form of orally disintegrating tablets and oral solution is bioequivalent to film-coated tablets.

Risperidone is metabolized to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to that of risperidone.

Absorption.

After oral administration, risperidone is completely absorbed and reaches peak plasma concentrations within 1–2 hours; in elderly patients, peak concentrations are reached within 2–3 hours. Absolute bioavailability after oral administration of risperidone is 70% (CV = 25%). Food does not affect drug absorption; therefore, risperidone can be administered independently of meals. 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 blood plasma, risperidone binds to albumin and acid 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 achieved within 4–5 days.

Biotransformation and elimination.

Risperidone is metabolized by cytochrome CYP2D6 to 9-hydroxyrisperidone, which exerts a pharmacological effect similar to risperidone. Risperidone and 9-hydroxyrisperidone together form the active antipsychotic fraction.

Cytochrome CYP2D6 is subject to genetic polymorphism. In rapid metabolizers of CYP2D6, risperidone is rapidly converted to 9-hydroxyrisperidone, whereas in slow metabolizers, the conversion occurs much more slowly. Although concentrations of risperidone and 9-hydroxyrisperidone are lower in rapid metabolizers than in slow metabolizers, the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone (i.e., the active antipsychotic fraction) after single and multiple doses are similar in both rapid and slow metabolizers of cytochrome CYP2D6.

Another metabolic pathway of risperidone is N-dealkylation. In vitro studies using human liver microsomes have shown that risperidone, at clinically relevant concentrations, does not significantly inhibit the metabolism of drugs metabolized by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. One week after drug administration, 70% of the dose is excreted in urine and 14% in feces. The concentration of risperidone and 9-hydroxyrisperidone in urine accounts for 35–45% of the administered dose. The remainder consists of inactive metabolites. After oral administration in patients with psychosis, the elimination half-life is approximately 3 hours. The half-life of 9-hydroxyrisperidone and the active antipsychotic fraction reaches 24 hours, and in elderly patients, it is 34 hours.

Linearity.

Plasma concentrations of risperidone are proportional to the dose of the drug (within the therapeutic dose range).

Elderly patients and patients with renal or hepatic impairment.

A pharmacokinetic study of single-dose administration in elderly patients demonstrated that 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 adult patients with severe renal impairment, clearance was ~31% of that in adults without renal impairment. The elimination half-life of the active fraction was 16.7 hours in young adults, 24.9 hours in adults with moderate renal impairment (approximately 1.5 times longer than in young adults), and 28.8 hours in patients with severe renal impairment (approximately 1.7 times longer than in young adults). In patients with hepatic insufficiency, normal plasma concentrations of risperidone were observed, but the mean value of the free fraction of risperidone in plasma was increased by 37.1%.

After oral administration, the clearance and elimination half-life of risperidone and the active antipsychotic fraction in patients with moderate to severe hepatic impairment did not differ significantly from those in young healthy volunteers.

Children.

The pharmacokinetics of risperidone, 9-hydroxyrisperidone, and the active antipsychotic fraction in children are similar to those in adults.

Gender, race, and smoking.

Population pharmacokinetic analysis did not reveal any significant influence of gender, 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 risk of harm to self or others and lack of response to non-pharmacological treatment approaches (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 intellectual development below average or intellectual disability diagnosed according to DSM-IV criteria, in whom 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 Relprevide® be prescribed by a specialist in pediatric neurology, child and adolescent psychiatry, or by a physician experienced in managing behavioral disorders in children and adolescents.

Contraindications.

Hypersensitivity to the active ingredient or to any of the excipients of the medicinal product.

Dementia and symptoms of Parkinson's disease (rigidity, bradykinesia, and parkinsonian postural disturbances).

Dementia and suspected dementia with Lewy bodies (in addition to dementia symptoms, at least two of the following symptoms: 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, such as antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), certain antihistamines, other antipsychotics, certain antimalarials (quinine, mefloquine), and agents 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 increased risk of sedation.

Levodopa and dopamine agonists.

Relprevide® may exhibit antagonistic effects towards 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.

During the post-marketing period, cases of clinically significant hypotension were observed with concomitant use of risperidone and antihypertensive medicinal products.

Psychostimulants.

Use of risperidone in combination with psychostimulants (e.g., methylphenidate) may lead to the emergence of extrapyramidal symptoms after dose adjustment of one or both agents (see section "Special precautions").

Paliperidone.

Concomitant use of oral Relprevide® with paliperidone is not recommended, as paliperidone is the active metabolite of risperidone and their combination may result in additive effects of the active antipsychotic fraction.

Pharmacokinetic interactions.

Food does not affect absorption of Relprevide®.

Relprevide® is primarily metabolized via CYP2D6 and to a lesser extent via CYP3A4. Relprevide® 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 Relprevide® with a potent CYP2D6 inhibitor may increase plasma concentrations of risperidone, but to a lesser extent than the active antipsychotic fraction. Higher doses of potent CYP2D6 inhibitors (e.g., paroxetine, see below) may increase plasma concentrations of the active antipsychotic fraction of risperidone. Other CYP2D6 inhibitors such as quinidine are expected to affect plasma concentrations of risperidone similarly. At the initiation of concomitant therapy, and upon discontinuation of paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at high doses, the physician should review the dose of Relprevide®.

CYP3A4 and P-gp inhibitors.

Concomitant use of Relprevide® with potent inhibitors of CYP3A4 and/or P-gp may substantially increase plasma concentrations of the active antipsychotic fraction of risperidone. At the initiation of concomitant therapy, and upon discontinuation of itraconazole or other potent CYP3A4 and/or P-glycoprotein inhibitors, the physician should review the dose of Relprevide®.

CYP3A4 and P-gp inducers.

Concomitant use of Relprevide® 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 CYP3A4/P-glycoprotein inducers, the physician should review the dose of Relprevide®. The effect of CYP3A4 inducers depends on duration, with maximum impact achieved at least 2 weeks after initiation of treatment. Accordingly, after discontinuation of inducers, 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 protein binding has not been observed. When used concomitantly with such medicinal products, the prescribing information of the co-administered drug should be consulted regarding metabolic pathways and need for dose adjustment.

Children.

Interaction studies have been conducted only in adult patients. It is unknown whether the results obtained can be extrapolated to children.

Concomitant use of psychostimulants (e.g., methylphenidate) with Relprevide® in children did not affect the pharmacokinetics or efficacy of Relprevide®.

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 been shown to reduce plasma concentrations of the active antipsychotic fraction of risperidone. A similar effect may occur with phenytoin and phenobarbital, which are also inducers of hepatic enzymes CYP3A4 and P-glycoprotein.
• Topiramate moderately reduces bioavailability of risperidone but does not affect bioavailability of the active antipsychotic fraction. It is unlikely that this interaction will 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 co-administered 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 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-boosted protease inhibitors may increase plasma concentrations of the active antipsychotic fraction of risperidone.

Beta-blockers

• Some beta-blockers may increase plasma concentrations of risperidone, but do not affect plasma concentrations of the active antipsychotic fraction.

Calcium channel blockers

• Verapamil, a moderate 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 bioavailability of risperidone and minimally affect bioavailability of the active antipsychotic fraction.

Selective serotonin reuptake inhibitors (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 concentrations 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

• Relprevide® has no clinically significant effect on the pharmacokinetics of valproate or topiramate.

Antipsychotic medicinal products

• Aripiprazole, a substrate of CYP2D6 and CYP3A4: oral or injectable formulations of risperidone do not affect the pharmacokinetics of aripiprazole or its active metabolite dehydroaripiprazole.

Cardiac glycosides

• Relprevide® has no clinically significant effect on the pharmacokinetics of digoxin.

Lithium

• Relprevide® has no clinically significant effect on the pharmacokinetics of lithium.

Concomitant use of risperidone with furosemide.

See section "Special precautions" regarding increased mortality in elderly patients with dementia when used concomitantly with furosemide.

Special precautions for use.

Geriatric patients with dementia

Increased mortality.

An increased mortality rate has been observed in elderly patients with dementia treated with atypical antipsychotic drugs compared to placebo-treated patients in a meta-analysis of 17 controlled studies of atypical antipsychotics, including risperidone.

In a placebo-controlled study using risperidone in this patient population, the incidence of fatal events was 4.0% compared to 3.1% in the placebo group. The mean age of patients who died was 86 years (range: 67–100 years).

Data from two large observational studies indicate that elderly people with dementia treated with conventional (typical) antipsychotics have a slightly higher risk of death compared to patients who did not receive antipsychotics. Based on available study data, the exact level of this risk cannot be determined, and the reason for the increased risk is unknown.

Concomitant use with furosemide.

An increased mortality rate was observed in elderly patients with dementia receiving concomitant furosemide and risperidone (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) in a placebo-controlled study. Increased mortality in patients treated with furosemide concomitantly with risperidone was observed in two out of four clinical trials.

No increased mortality rate was observed in patients who received risperidone concomitantly with other diuretics (mainly thiazide diuretics administered at low doses).

The pathophysiological mechanisms underlying this observation have not been established. The cause of death was also not uniform. However, particular caution should be exercised when prescribing the drug in such cases, and the risks and benefits of this combination or combinations with other potential diuretics should be carefully evaluated before administration. No increased mortality was observed among patients who received risperidone with other diuretics. Regardless of treatment, dehydration was a common risk factor for mortality and should be carefully monitored in patients with dementia.

Cerebrovascular adverse effects (CAEs).

In placebo-controlled clinical trials in patients with dementia treated with risperidone, a higher incidence of cerebrovascular adverse effects (cerebrovascular events and transient ischemic attacks), including fatal outcomes, was observed compared to those receiving placebo (mean age: 85 years; age range: 73–97 years).

Pooled data from six placebo-controlled studies in elderly patients with dementia (aged 65 years and older) demonstrated cerebrovascular disorders in 3.3% (33/989) of patients treated with risperidone compared to 1.2% (8/693) of patients receiving placebo. The odds ratio between the Relprevv® and placebo groups [odds ratio; 95% confidence interval (CI)] was 2.96 (1.34; 7.50).

The mechanism of this increased risk is unknown. An increased risk of CAEs cannot be ruled out for other antipsychotics or other patient groups. Relprevv® 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 treatment 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 cardiovascular events such as sudden weakness, facial, arm, or leg numbness, speech disturbances, and visual disturbances. All possible treatment options, including discontinuation of risperidone therapy, should be promptly considered.

For persistent aggression in patients with moderate to severe Alzheimer's disease, Relprevv® 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.

Patients should be regularly assessed during treatment, and the need for continued therapy should be periodically reviewed.

Orthostatic hypotension.

Due to the α1-blocking activity of risperidone, orthostatic hypotension may occur, especially at the beginning of treatment. Clinically significant hypotension has been observed during post-marketing use when risperidone was co-administered with antihypertensive agents. Risperidone should be used with caution in patients with known cardiovascular disorders (such as heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disorders). In such cases, dose titration should be performed (see section "Dosage and administration"). Dose reduction should be considered if hypotension occurs.

Leukopenia, neutropenia, agranulocytosis.

Cases of leukopenia, neutropenia, and agranulocytosis have been reported during treatment with antipsychotic agents, including risperidone. Agranulocytosis has been observed very rarely (<1/10,000 patients).

Patients with a history of clinically significant leukopenia or medication-induced leukopenia/neutropenia should be closely monitored during the first few months of treatment, and risperidone should be discontinued at the first sign of significant leukopenia if no other cause is identified.

Patients with clinically significant neutropenia should be monitored for fever and other signs of infection and treated appropriately if symptoms occur. In cases of severe neutropenia (<1×10⁹/L), risperidone treatment should be discontinued, and white blood cell counts should be monitored until recovery.

Late dyskinesia / extrapyramidal symptoms.

With drugs possessing dopamine receptor antagonist properties, late dyskinesia characterized by involuntary rhythmic movements (predominantly of the tongue and/or face) may occur. The occurrence of extrapyramidal symptoms is a risk factor for the development of late dyskinesia. If signs and symptoms of late dyskinesia appear, discontinuation of all antipsychotic drugs should be considered.

Caution is advised when co-administering psychostimulants (e.g., methylphenidate) with risperidone, as extrapyramidal symptoms may occur when adjusting the dose of either or both drugs. Gradual discontinuation of psychostimulant therapy is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Neuroleptic malignant syndrome.

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 signs include myoglobinuria (rhabdomyolysis) and acute renal failure. If neuroleptic malignant syndrome develops, all antipsychotic drugs, including Relprevv®, must be discontinued.

Parkinson's disease and dementia with Lewy bodies.

Physicians should carefully weigh the risks and benefits of prescribing antipsychotic agents, including risperidone, to 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, blunted pain sensitivity, postural instability with frequent falls, in addition to extrapyramidal symptoms).

Hyperglycemia and diabetes mellitus.

Hyperglycemia, diabetes mellitus, or worsening of pre-existing diabetes has been reported during treatment with Relprevv®. In some cases, prior obesity, 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 Relprevv®, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness), and diabetic patients should be regularly evaluated for worsening glucose control.

Weight gain.

Significant weight gain has been reported with Relprevv®. Regular body weight monitoring is recommended.

Hyperprolactinemia.

Hyperprolactinemia is a common adverse effect of risperidone treatment. Patients with adverse effects potentially related to plasma prolactin levels (e.g., gynecomastia, menstrual disorders, anovulation, fertility disorders, decreased libido, erectile dysfunction, 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 between antipsychotic use and breast cancer has not been established in clinical and epidemiological studies, risperidone should be prescribed with caution in patients with relevant medical history. Relprevv® should be used cautiously in patients with existing hyperprolactinemia and in those with prolactin-dependent tumors.

QT interval prolongation.

QT interval prolongation has been reported very rarely in the post-marketing period. As with other 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 co-administered with other medicinal products that prolong the QT interval.

Seizures.

Relprevv® should be prescribed 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.

Thermoregulation.

Antipsychotic drugs may impair the body's ability to reduce core body temperature. Appropriate care is recommended for patients receiving risperidone who are exposed to conditions that may elevate core body temperature, such as intense physical exercise, exposure to high ambient temperatures, concomitant therapy with anticholinergic drugs, or dehydration.

Antiemetic effect.

Preclinical studies have shown risperidone to have antiemetic properties. This property may mask symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye's syndrome, and brain tumors.

Hepatic and renal function impairment.

Patients with impaired renal function have reduced ability to eliminate the active antipsychotic fraction compared to adults with normal renal function. In patients with impaired hepatic function, increased plasma concentrations of free risperidone have been observed (see section "Dosage and administration").

Venous thromboembolism.

Cases of venous thromboembolism have been reported with antipsychotic drugs. Since patients treated with antipsychotics often have acquired risk factors for venous thromboembolism, all possible risk factors for thromboembolism should be identified before and during risperidone treatment, and appropriate preventive measures should be taken.

Intraoperative floppy iris syndrome (IFIS).

Intraoperative floppy iris syndrome has been observed during cataract surgery in patients treated with α1-adrenergic receptor antagonists, including risperidone.

IFIS increases the risk of ocular complications during and after surgery. The ophthalmic surgeon should be informed about current or past use of antipsychotic drugs. The potential benefits of discontinuing α1-blocking agents before surgery have not been established—risks of discontinuing antipsychotic therapy should be carefully weighed.

Children.

Before prescribing Relprevv® 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 its potential impact on learning ability.

Adjusting the timing of risperidone administration may improve sedation's impact on attention and concentration in children and adolescents.

Risperidone use has been associated with a slight increase in body weight and body mass index (BMI). Initial body weight measurement before treatment 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, 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, data from this study are insufficient to determine whether risperidone affects final adult height, whether measurement results directly depend on risperidone's effect on bone growth, or whether the underlying disease or improved disease control contributes to increased 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.

Relprevv® coated tablets contain lactose. Patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not take Relprevv® coated tablets. Relprevv® coated tablets should be used with caution in patients hypersensitive to excipients and inhibitors of prostaglandin synthesis.

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, abnormally increased or decreased muscle tone, tremor, drowsiness, respiratory disturbances, or feeding difficulties. These complications may vary in severity. Therefore, newborns should be carefully monitored.

Relprevv® is not recommended during pregnancy except in cases of vital necessity. If discontinuation of Relprevv® treatment during pregnancy is necessary, 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 potential risks to the infant should be carefully weighed.

Fertility (reproductive capacity).

Like other dopamine D2-receptor antagonists, risperidone increases prolactin levels.

Hyperprolactinemia may reduce hypothalamic secretion of gonadotropin-releasing hormone (GnRH), leading to decreased pituitary gonadotropin secretion. This may negatively affect reproductive function in both women and men due to impaired gonadal steroidogenesis. No such effects were observed in preclinical studies.

Ability to influence reaction speed when driving or operating machinery.

Relprevv® may have a minor or moderate effect on the ability to drive due to its potential impact on the nervous system and visual organs (see section "Adverse reactions"). During treatment, patients should refrain from driving or operating machinery until their individual response to the drug is known.

Method of Administration and Dosage.

Dosage

Schizophrenia

Adults

Relprevide® may be administered once or twice daily.

Treatment should be initiated at 2 mg of Relprevide® per day; on the second day, the dose may be increased to 4 mg. Thereafter, the dose may be maintained unchanged or, if necessary, further individual dose adjustments may be made.

The recommended dose for most patients is 4–6 mg per day. Some patients may require gradual dose escalation or a reduced initial and maintenance dose.

Doses exceeding 10 mg of risperidone per day have not demonstrated greater efficacy compared to lower doses but may lead to the emergence of extrapyramidal symptoms.

The safety of doses above 16 mg per day has not been studied.

Elderly patients (aged 65 years and older)

The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily.

Children

The use of this medicinal product is not recommended in children (under 18 years of age).

Manic episodes in bipolar disorder

Adults

The recommended initial dose of Relprevide® is 2 mg once daily. The dose may be individually increased by increments of 1 mg/day no more frequently than every 24 hours. The recommended dose range is 1 to 6 mg per day. The use of risperidone at doses exceeding 6 mg per day in patients with manic episodes has not been studied.

As with other forms of symptomatic treatment, long-term use of Relprevide® should be periodically reviewed and adjusted throughout therapy.

Elderly patients (aged 65 years and older)

The recommended initial dose is 0.5 mg twice daily. If necessary, the dose may be increased to 1–2 mg twice daily, increasing by 0.5 mg twice daily. Since experience in elderly patients is limited, caution is recommended when administering the drug.

Children

The use of this medicinal product is not recommended in children (under 18 years of age).

Short-term treatment of marked aggression or severe psychiatric symptoms in patients with Alzheimer's type dementia

The recommended initial dose is 0.25 mg twice daily. If necessary, the dose may be increased by increments of 0.25 mg twice daily, no more frequently than every other day. For most patients, the optimal dose is 0.5 mg twice daily. However, for some patients, the dose may be increased to 1 mg twice daily. Relprevide® 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 Relprevide® 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 increments of 0.5 mg once daily, no more frequently than every other day. The optimal dose for most patients is 1 mg once daily. However, for some patients, a dose of no more than 0.5 mg once daily may be sufficient to achieve a beneficial effect, while others may require 1.5 mg once daily.

Patients with body weight < 50 kg

The recommended initial dose is 0.25 mg once daily. If necessary, the dose may be adjusted by increments of 0.25 mg once daily, no more frequently than every other day. The optimal dose for most patients is 0.5 mg once daily. However, for some patients, a dose of no more than 0.25 mg once daily may be sufficient to achieve a beneficial effect, while others may require 0.75 mg once daily.

As with other forms of symptomatic treatment, long-term use of Relprevide® should be periodically reviewed and adjusted throughout therapy.

Children

The use of this medicinal product is not recommended in children under 5 years of age.

Patients with hepatic and renal impairment

In patients with impaired renal function, the active antipsychotic fraction is eliminated more slowly than in patients with normal renal function. In patients with impaired hepatic function, the concentration of the free fraction of risperidone in plasma is increased.

Regardless of the condition being treated, all initial and subsequent doses of risperidone should be halved. Dose escalation should proceed more slowly in these patients.

Relprevide® should be used with caution in this patient population.

Method of Administration

Relprevide® is intended for oral administration. Food intake does not affect the absorption of Relprevide®.

At the end of treatment, gradual discontinuation of the medicinal product is recommended. After abrupt discontinuation of high doses of antipsychotic agents, isolated cases of acute withdrawal symptoms have been observed, including nausea, vomiting, sweating, and insomnia (see section "Adverse Reactions"). Psychotic symptoms may also recur, and cases of involuntary movements (such as akathisia, dystonia, and dyskinesia) have been reported.

Switching from therapy with other antipsychotic agents

If clinically justified, it is recommended to gradually discontinue previous therapy with other medicinal products when initiating treatment with risperidone. In patients switching from depot antipsychotic therapy, treatment with risperidone should be initiated instead of the next scheduled injection. The need for continued use of anti-Parkinson drugs should be periodically evaluated.

Children

Relprevide® is used for the treatment of marked aggression in behavioral disorders in children aged 5 years and older.

Overdose. Symptoms.
Signs and symptoms observed in overdose are known adverse reactions of 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 in cases of overdose. Atrial flutter associated with risperidone overdose in combination with paroxetine has been reported.

In cases of acute overdose, potential drug interactions involving 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.

Relprevide® has no specific antidote. Therefore, appropriate supportive measures should be implemented. 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 observation and monitoring should be maintained until the patient recovers.

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.

a Hyperprolactinemia in some cases may lead to gynecomastia, menstrual disorders, amenorrhea, anovulation, galactorrhea, impaired fertility, decreased libido, and erectile dysfunction.

b During placebo-controlled studies, diabetes mellitus was reported in 0.18% of patients receiving risperidone compared to 0.11% in the placebo group. The overall incidence across all clinical trials was 0.43% among patients treated with risperidone.

c Not observed in clinical studies of Relprevide®, but identified during post-marketing surveillance.

d Extrapyramidal disorders include: parkinsonism (hypersalivation, muscle rigidity, parkinsonism, sialorrhea, 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, ocular movement, tongue paralysis, tic (in the facial area), laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotonus, lingual 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 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 observed with paliperidone use, which may also potentially occur with Relprevide®.

Adverse reactions common to antipsychotic medicinal products

QT interval prolongation

As with other antipsychotics, QT interval prolongation has been reported during the post-marketing period with risperidone use. Other cardiac adverse reactions associated with QT prolongation have also been reported with antipsychotic use, such as ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and atrial flutter-fibrillation.

Venous thromboembolism

Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported during antipsychotic treatment.

Weight gain

Comparison of the number of patients treated with risperidone versus placebo who experienced a body weight increase of 7% in placebo-controlled trials lasting 6 to 8 weeks showed a statistically significant difference in the frequency of weight gain in the risperidone group (18%) compared to the placebo group (9%). In three-week placebo-controlled trials in adult patients with acute mania, the frequency of weight gain ≥7% was similar in the risperidone group (2.5%) and the placebo group (2.4%), and slightly higher in the active control group (3.5%).

In 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. 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 on specific patient categories

Adverse reactions reported more frequently in elderly patients with dementia or in children than in adult patients are described below.

Elderly patients with dementia

Transient ischemic attack and cerebrovascular disorders were adverse reactions reported during clinical trials with frequencies of 1.4% and 1.5%, respectively, in elderly patients with dementia. Additionally, the following adverse reactions were reported with a frequency ≥5% in elderly patients with dementia and at least twice as high as in other adult patient groups: urinary tract infections, peripheral edema, lethargy, and cough.

Children

Overall, the expected adverse reactions in children are similar to those in adults in terms of frequency, type, and severity.

Adverse reactions observed in children (aged 5 to 17 years) with a frequency ≥5% and at least twice as high as in adult patients include: somnolence/sedation, increased fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhea, and enuresis. The long-term impact of risperidone treatment on sexual maturation and growth has not been fully studied (see section "Special precautions for use").

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging.

10 tablets per blister; 1, 2, or 6 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Egis Pharmaceuticals Ltd.

Manufacturer’s location and address of place of business.

1165 Budapest, Bekkerveldi Street 118-120, Hungary.