Eperon

Risperidone.

Each Eperon film-coated tablet contains 1mg risperidone.
Each Eperon film-coated tablet contains 2mg risperidone.
Each Eperon 1/2 mg film-coated tablet contains 117.8/116.8mg lactose monohydrate respectively.
Each Eperon 2 mg film-coated tablet contains 0.034mg of Sunset Yellow (E110).
The tablet can be divided into equal halves.
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate, Maize starch, Sodium lauryl sulphate, Cellulose microcrystalline, Hypromellose, Silicon dioxide colloidal, Magnesium stearate.
Film coating: Hypromellose, Titanium dioxide (E171), Propylene glycol, Talc.
Additional excipients: 1 mg: Opadry White: Titanium dioxide (E171).
2 mg: Opadry Orange: Sunset Yellow FCF Aluminium lake (E110).

Pharmacotherapeutic Group: Other antipsychotics. ATC code: NO5AX08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Risperidone is a selective monoaminergic antagonist with a high affinity for both serotonergic 5-HT₂ and dopaminergic D₂ receptors. Risperidone binds also to alpha₁-adrenergic receptors and, with lower affinity, to H₁-histaminergic and alpha₂-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D₂ antagonist, that is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical neuroleptics. Balanced central serotonin and dopamine antagonism may reduce the tendency to cause extrapyramidal side effects, and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Pharmacokinetics: Absorption: Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absorption is not affected by food and thus risperidone can be given with or without meals.
Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 l/kg. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein.
The plasma protein binding of risperidone is 88%, that of 9-hydroxy-risperidone is 77%.
One week after administration, 70% of the dose is excreted in the urine and 14% in the feces.
In urine, risperidone plus 9-hydroxy-risperidone represent 35-45% of the dose. The remainder is inactive metabolites.
Metabolism: Risperidone is metabolized by CYP2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity as risperidone.
Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. Another metabolic pathway of risperidone is N-dealkylation.
Elimination: After oral administration to psychotic patients, risperidone is eliminated with a half-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours.
Dose Proportionality: Steady-state of risperidone is reached within 1 day in most patients. Steady-state of 9-hydroxy-risperidone is reached within 4-5 days of dosing.
Risperidone plasma concentrations are dose-proportional within the therapeutic dose-range.
Special Populations: Pediatrics: The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children are similar to those in adults.
Renal and Hepatic Impairment: A single-dose study showed higher active plasma concentrations and a reduced clearance of the active antipsychotic fraction by 30% in the elderly and 60% in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by about 35%.
Toxicology: Preclinical safety data: In (sub)chronic toxicity studies, in which dosing was started in sexually immature rats and dogs, dose-dependent effects were present in male and female genital tract and mammary gland.
These effects were related to the increased serum prolactin levels, resulting from the dopamine D2-receptor blocking activity of risperidone. In a toxicity study with juvenile rats, increased pup mortality and a delay in physical development was observed.
In a 40-week study with juvenile dogs, sexual maturation was delayed. Long bone growth was not affected at a dose similar to the maximum human dose in adolescents (6 mg/day); effects were observed at a dose 4-fold (on an AUC basis) or 7-fold (on a mg/m² basis) the maximum human dose in adolescents.
All other safety data relevant to the prescriber have been included in the appropriate section.

Eperon is indicated for the treatment of a broad range of patients with schizophrenia, including first episode psychoses, acute schizophrenic exacerbations, chronic schizophrenia, and other psychotic conditions, in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), and/or negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech) are prominent. Eperon alleviates affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia. Eperon is also effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
Risperidone is indicated for the short-term treatment of persistent aggression in patients with moderate to severe dementia of the Alzheimer's type unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.
Eperon is indicated for the treatment of behavioural disorders associated with autism (eg irritability, social withdrawal, stereotypic behaviour, hyperactivity and inappropriate speech) in children and adolescents.
Eperon is also indicated for bipolar mania.
Adjunctive therapy: Eperon is indicated as adjunctive therapy to mood stabilizers in the treatment of manic episodes associated with bipolar disorders. These episodes are characterized by symptoms such as elevated, expansive or irritable mood, inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility, or poor judgment, including disruptive or aggressive behaviors.
Monotherapy: Eperon is indicated in the treatment of acute manic episodes associated with bipolar 1 disorder. The effectiveness of Eperon for more than 12 weeks of treatment of an acute episode, and for the prevention of new manic episodes has not been established. Eperon is indicated in the treatment of conduct and other disruptive behavior disorders in children (over 5 years), adolescents and adults with subaverage intellectual functioning or mental retardation in whom destructive behaviors (e.g. aggression, impulsivity and self-injurious behaviors) are prominent.

Schizophrenia: Adults: Eperon may be given once daily or twice daily. Patients should start with 2 mg/day risperidone. The dosage may be increased on the second day to 4 mg. Subsequently, the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.
Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and may cause increased incidence of extrapyramidal symptoms. Safety of doses above 16 mg/day has not been evaluated, and is therefore not recommended.
Elderly: A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily.
Paediatric population: Risperidone is not recommended for use in children below age 18 with schizophrenia due to a lack of data on efficacy.
Manic episodes in bipolar disorder: Adults: Eperon should be administered on a once daily schedule, starting with 2 or 3 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. A dosing range between 2-6 mg per day is recommended. The physician who elects to use Eperon for periods extending beyond 12 weeks should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Elderly: A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2mg twice daily. Since clinical experience in elderly is limited, caution should be exercised.
Paediatric population: Risperidone is not recommended for use in children below age 18 with bipolar mania due to a lack of data on efficacy.
Behavioral Disturbances in patients with Dementia: A starting dose of 0.25 mg twice daily is recommended.
This dosage can be individually adjusted by increments of 0.25 mg twice daily, not more frequently than every other day, if needed.
The optimum dose is 0.5 mg twice daily for most patients. Some patients, however, may benefit from doses up to 1 mg twice daily.
Conduct disorder: Children and adolescents from 5 to 18 years of age: For subjects ≥ 50 kg, a starting dose of 0.5 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.5 mg once daily not more frequently than every other day, if needed. The optimum dose is 1 mg once daily for most patients. Some patients, however, may benefit from 0.5 mg once daily while others may require 1.5 mg once daily.
For subjects <50 kg, a starting dose of 0.25 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg once daily not more frequently than every other day, if needed. The optimum dose is 0.5 mg once daily for most patients. Some patients, however, may benefit from 0.25 mg once daily while others may require 0.75 mg once daily.
As with all symptomatic treatments, the continued use of Eperon must be evaluated and justified on an ongoing basis.
Eperon is not recommended in children less than 5 years of age, as there is no experience in children less than 5 years of age with this disorder.
Autism: Pediatrics (5-17 years of age): The dosage of risperidone should be individualized according to the needs and response of the patient. Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients ≥ 20 kg.
On Day 4, the dose may be increased by 0.25 mg for patients < 20 kg and 0.5 mg for patients ≥ 20 kg.
This dose should be maintained and response should be assessed at approximately Day 14. Only in patients not achieving sufficient clinical response should additional dose increases be considered. Dose increases may proceed at ≥ 2-week intervals in increments of 0.25 mg for patients < 20 kg or 0.5 mg for patients ≥ 20 kg.
In clinical studies, the maximum dose studied did not exceed a total daily dose of 1.5 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or 3.5 mg in patients > 45 kg. Doses below 0.25mg/day were not effective in clinical studies. (See Table 1.)

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For prescribers preferring to dose on a mg/kg/day basis the following guidance is provided. (See Table 2.)

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Risperidone can be administered once daily or twice daily. Patients experiencing somnolence may benefit from a switch in dosing from once daily to either once daily at bedtime or twice daily. Once sufficient clinical response has been achieved and maintained, consideration may be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. Experience is lacking in children less than 5 years and limited in autistic adolescents. Effectiveness for more than 8 weeks has not been systematically evaluated in double-blind, parallel-controlled clinical trials. Therefore, the physician who elects to use risperidone for the treatment of behavioral disorders associated with autism (eg irritability, social withdrawal, stereotypic behaviour, hyperactivity and inappropriated speech) in children and adolescents for extended periods should periodically re-evaluate the long term risks and benefits of the drug for the individual patient.
Hepatic and renal impairment: Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than in adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.
Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal or hepatic impairment.
Eperon should be used with caution in these groups of patients.
Method of administration: Eperon is for oral use. Food does not affect the absorption of Eperon.
Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic medicines (see Adverse Reactions). Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported.
Switching from other antipsychotic: When medically appropriate, gradual discontinuation of the previous treatment while Eperon therapy is initiated is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate Eperon therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medicines should be re-evaluated periodically.

Symptoms: In general, reported signs and symptoms have been those resulting from an exaggeration of the known pharmacological effects of risperidone.
These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.
In overdose, QT-prolongation and convulsions have been reported. Torsade de Pointes has been reported in association with combined overdose of risperidone and paroxetine.
In case of acute overdose, the possibility of multiple drug involvement should be considered.
Treatment: Symptomatic. Establish and maintain a clear airway, and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered only when drug intake was less than one hour before.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to Eperon.
Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, an anticholinergic medicinal product should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Hypersensitivity to risperidone or to any of the excipients.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Eperon and preventive measures undertaken.
Concomitant use with furosemide: In the risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70-96) or furosemide alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.
No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.
Cerebrovascular Adverse Events (CAE): In placebo-controlled trials in elderly patients with dementia there was a significantly higher incidence (approximately 3-fold increased) of CVAEs, such as stroke (including fatalities) and transient ischaemic attack in patients treated with risperidone compared with patients treated with placebo (mean age 85 years; range 73 to 97). The pooled data from six placebo-controlled studies in mainly elderly patients (>65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1009) of patients treated with risperidone and 1.2% (8/712) of patients treated with placebo. The odds ratio (95% exact confidence interval) was 2.96 (1.34, 7.50). The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Eperon should be used with caution in patients with risk factors for stroke.
The risk of CVAEs was higher in patients on risperidone with mixed or vascular type of dementia when compared to Alzheimer's dementia.
Physicians are advised to assess the risks and benefits of the use of risperidone in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be cautioned to immediately report signs and symptoms of potential CVAEs, such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems. All treatment options should be considered without delay, including discontinuation of risperidone.
Patients should be re-assessed regularly to determine the need for continued treatment.
Orthostatic hypotension: Due to the alpha-blocking activity of risperidone, orthostatic hypotension can occur, especially during the initial dose-titration period. Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. Eperon should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see Dosage & Administration). A dose reduction should be considered if hypotension occurs.
Leukopenia, Neutropenia, and Agranulocytosis: Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including Eperon. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during past-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Eperon should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1 X 10⁹/L) should discontinue Eperon and have their WBC followed until recovery.
Venous Thromboembolism: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Eperon and preventive measures undertaken.
Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS): Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, characterized by rhythmical involuntary movements, predominantly of the tongue and/or face. The onset of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.
Neuroleptic Malignant Syndrome (NMS): Neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event all antipsychotic drugs including risperidone should be discontinued.
Parkinson's disease and dementia with Lewy bodies: Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including Eperon, to patients with Parkinson's disease or Dementia with Lewy Bodies (DLB). Parkinson's disease may worsen with risperidone. Both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medicinal products; these patients were excluded from clinical trials. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported in patients treated with atypical antipsychotics, including Eperon. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. Any patient treated with atypical antipsychotics, including Eperon should be monitored for symptoms of hyperglycemia and diabetes mellitus (see Adverse Reactions).
However, epidemiological studies suggest an increased risk of diabetes and hyperglycaemia with atypical antipsychotics.
Patients with an established diagnosis of diabetes mellitus, risk factors for diabetes (eg obesity, family history of diabetes), or those who develop symptoms of hyperglycaemia during treatment with a typical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness.
Weight Gain: Significant weight gain has been reported. Monitoring weight gain is advisable when Eperon is being used.
QT Interval: As with other antipsychotics, caution should be exercised when Eperon is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome and in concomitant use with drugs known to prolong the QT interval.
Priapism: Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with Eperon during postmarketing surveillance (see Adverse Reactions).
Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including Eperon see Adverse Reactions).
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.
Seizures: As with other antipsychotic drugs, Eperon should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Body temperature regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing Eperon, to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant treatment with anticholinergic activity, or being subject to dehydration.
Antiemetic Effect: An antiemetc effect was observed in preclinical studies with risperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor.
Excipients: The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sunset yellow which is contained in Eperon 2 mg film-coated tablets may cause allergic reactions.
Effects on ability to drive and use machines: Eperon can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see Adverse Reactions). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
Elderly patients with dementia: Overall mortality: Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4.0% for risperidone-treated patients compared to 3.1% for placebo-treated patients. The odds ratio (95% exact confidence interval) was 1.21 (0.7, 2.1). The mean age (range) of patients who died was 86 years (range 67-100).

Pregnancy: There are no adequate data from the use of risperidone in pregnant women. Neonates exposed to antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder.
Consequently, newborns should be monitored carefully. Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen (see Pharmacology: Toxicology: Preclinical safety data under Actions).
The potential risk for humans is unknown.
Therefore, Eperon should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.
Lactation: In animal studies, risperidone and 9-hydroxyrisperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxyrisperidone are also excreted in human breast milk in small quantities. Therefore, women receiving Eperon should not breast-feed.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of risperidone based on the comprehensive assessment of the available adverse event information. A causal relationship with risperidone usually cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trial Data: The safety of risperidone was evaluated from a clinical trial database consisting of 9803 patients exposed to one or more doses of risperidone for the treatment of various psychiatric disorders in adults, elderly patients with dementia, and pediatrics.
Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures.
The majority of all adverse reactions were mild to moderate in severity.
Double-Blind, Placebo-Controlled Data - Adult Patients: Adverse reactions reported by ≥ 1% of risperidone-treated adult patients in nine 3- to 8-week double-blind, placebo-controlled trials are shown in Table 3. (See Table 3.)

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Double-Blind, Placebo-Controlled Data - Elderly Patients with Dementia: Adverse reactions reported by ≥ 1% of risperidone-treated elderly patients with dementia in six 4- to 12-week double-blind, placebo-controlled trials are shown in Table 4. Table 4 includes only those adverse reactions that are either not listed in Table 3 or those adverse reactions that occurred at ≥ 2 times the frequency of the adverse reactions listed in Table 3. (See Table 4.)

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Double-Blind, Placebo-Controlled Data - Pediatric Patients: Adverse reactions reported by > 1% of risperidone-treated pediatric patients in eight 3- to 8-week double-blind, placebo-controlled trials are shown in Table 5. Table 5 includes only those adverse reactions that are either not listed in Table 3 or those adverse reactions that occurred at ≥ 2 times the frequency of the adverse reactions listed in Table 3. (See Table 5.)

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Other Clinical Trial Data: Paliperidone is the active metabolite of risperidone, therefore the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. Hence, a comprehensive listing of adverse reactions across paliperidone and risperidone products provides relevant safety information for these related products. Adverse reactions detected for one formulation of risperidone or paliperidone were considered as relevant safety information for the other formulation of the same compound unless the adverse reaction was unique to either the formulation or the route of administration. Adverse reactions for one compound that were not listed for the other compound were also added to the label for the other compound unless no meaningful new safety information could be derived from the additional adverse reactions (ie. the term was vague or the medical concept was already found in the current label). All adverse reactions and their frequencies of occurrence in patients on risperidone are reflected in the Adverse Reactions tables as follows. (See Table 6.)

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Adverse reactions reported with risperidone and/or paliperidone by < 1% of risperidone-treated subjects in a pooled dataset of 23 double-blind, placebo-controlled pivotal studies (9 in adults, 6 in elderly patients with dementia, and 8 in pediatric patients) are shown in Table 7. (See Table 7.)

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Adverse reactions reported with risperidone and/or paliperidone in other clinical trials but not reported by risperidone-treated subjects in a pooled dataset of 23 double-blind, placebo-controlled pivotal studies are shown in Table 8. (See Table 8.)

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Postmarketing Data: Adverse events first identified as adverse reactions during postmarketing experience with risperidone and/or paliperidone are included in Tables 9.
In each table, the frequencies are provided according to the following convention: 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, including isolated reports.
In Table 9, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 9.)

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Pharmacodynamic-related Interactions: Centrally-acting Drugs and Alcohol: Given the primary CNS effects of Eperon, it should be used with caution in combination with other centrally acting drugs or alcohol.
Levodopa and Dopamine Agonists: Eperon may antagonize the effect of levodopa and other dopamine agonists.
Drugs with Hypotensive Effects: Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment.
Drugs Known to Prolong the QT interval: Caution is advised when prescribing Eperon with drugs known to prolong the QT interval.
Pharmacokinetic-related Interactions: Food does not affect the absorption of Eperon Risperidone is mainly metabolized through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9- hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.
Strong CYP2D6 Inhibitors: Co-administration of Eperon with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g., paroxetine, see as follows). When concomitant paroxetine or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, the physician should re-evaluate the dosing of Eperon.
CYP3A4 and/or P-gp Inhibitors: Coadministration of Eperon with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of Eperon.
CYP3A4 and/or P-gp Inducers: Co-administration of Eperon with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of Eperon.
Highly Protein-bound Drugs: When Eperon is taken together with other highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosages.
Pediatric Population: Interaction studies have only been performed in adults. The relevance of the results from these studies in pediatric patients is unknown.
Examples: Examples of drugs that may potentially interact or that were shown not to interact with risperidone are listed as follows: Antibacterials: Erythromycin, a CYP3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction.
Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentrations of the active antipsychotic fraction.
Anticholinesterases: Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.
Antiepileptics: Carbamazepine, a strong CYP3A4 inducer and P-gp inducer, has been shown to decrease the plasma levels of the active antipsychotic fraction of risperidone.
Topiramate modestly reduced the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.
Eperon does not show a clinically relevant effect on the phaimacokinetics of valproate or topiramate.
Antifungals: Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8mg/day.
Ketoconazole, a strong CYP3A4 inhibitor and a P­gp inhibitor, at a dosage of 200mg/day increased the plasma concentrations of risperidone and decreased the plasma concentration of 9-hydroxyrisperidone.
Antipsychotics: Phenothiazines, may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Aripiprazole, a CYP2D6 and CYP3A4 substrate: There is insufficient clinical evidence to evaluate the effect of risperidone, on the pharmacokinetics of the sum of aripiprazole and its active metabolite, dehydroaripiprazole.
Antivirals: Protease inhibitors: No formal study data are available; however, since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction.
Beta-Blockers: Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Calcium Channel Blockers: Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases the plasma concentration of risperidone and the active antipsychotic fraction.
Digitalis Glycosides: Risperidone does not show a clinically relevant effect on the pharmacokinetics of digoxin.
Diuretics: Furosemide: See Precautions regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.
Gastrointestinal Drugs: H2-receptor antagonists: Cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.
Lithium: Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium.
SSRIs and Tricyclic Antidepressants: Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but less so of the active antipsychotic fraction. Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentrations of risperidone, but, at dosages up to 20mg/day, less so of the active antipsychotic fraction. However, higher doses of paroxetine may elevate concentrations of the risperidone active antipsychotic fraction.
Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amytriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.

Special precautions for disposal: No special requirements.
Incompatibilities: Not applicable.

Store below 30°C in the original package.
Shelf-Life: 24 months.

Antipsychotics

N05AX08 - risperidone ; Belongs to the class of other antipsychotics.

POM