Risperdal/Risperdal Consta

Risperidone.

Risperdal: Tablets: Each tablet contains 1 mg or 2 mg of risperidone.
Oral Solution: The oral solution contains 1 mg/ml risperidone.
Risperdal Consta: RISPERDAL CONSTA is an extended release microspheres formulation of risperidone, composed of risperidone, composed of risperidone drug substance micro-encapsulated polylactide-co-glycolide, at a concentration of 381 mg risperidone per gram of microspheres.
Excipients/Inactive Ingredients: Risperdal: Tablets: Tablet core: Lactose monohydrate, Maize starch, Microcrystalline cellulose, Hypromellose 2910 15 mPa.s, Magnesium stearate, Colloidal anhydrous silica, Sodium lauryl sulfate. Film-coating: Hypromellose 2910 5 mPa.s, Propylene glycol, Titanium dioxide (only in 2 mg tablets), Talc (only in 2 mg tablets), Orange yellow S aluminum lake (only in 2 mg tablets).
Oral Solution: Tartaric acid, Benzoic acid, Sodium hydroxide, Purified water.
Risperdal Consta: Diluent: Polysorbate 20, carmellose sodium 40 mPa.s, disodium hydrogen phosphate dihydrate, anhydrous citric acid, sodium chloride, sodium hydroxide and water for injection.

Pharmacotherapeutic group: Other antipsychotics. ATC code: N05AX08.
Pharmacology: Mechanism of action: Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 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, which 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 extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Risperdal Consta: Clinical Trials: Schizophrenia: The effectiveness of Risperdal Consta (25 and 50 mg) in the management of manifestations of psychotic disorders (schizophrenia/schizoaffective disorder) was established in one 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.
In a 12-week comparative trial in stable patients with schizophrenia, RISPERDAL CONSTA was shown to be as effective as the oral tablet formulation. The long-term (50 weeks) safety and efficacy of RISPERDAL CONSTA was also evaluated in an open label trial of stable psychotic inpatients and outpatients who met the DSM IV criteria for schizophrenia or schizoaffective disorder. Over time efficacy was maintained with RISPERDAL CONSTA. (See Figures 1 and 2.)

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Maintenance Treatment in Bipolar I Disorder: Monotherapy: The effectiveness of RISPERDAL CONSTA for the maintenance treatment of Bipolar I Disorder was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I, who were stable on medications or experiencing an acute manic or mixed episode.
A total of 501 patients were treated during a 26-week open-label period with RISPERDAL CONSTA (starting dose of 25 mg, and titrated, if deemed clinically desirable, to 37.5 mg or 50 mg; in patients not tolerating the 25 mg dose, the dose could be reduced to 12.5 mg). In the open-label phase, 303 (60%) patients were judged to be stable and were randomized to double-blind treatment with either the same dose of RISPERDAL CONSTA or placebo and monitored for relapse. The primary endpoint was time to relapse to any mood episode (depression, mania, hypomania, or mixed).
Time to relapse was delayed in patients receiving RISPERDAL CONSTA monotherapy as compared to placebo. The majority of relapses were due to manic rather than depressive symptoms. Based on their bipolar disorder history, subjects entering this study had, on average, more manic episodes than depressive episodes.
Bipolar I Disorder: Adjunctive Therapy: The effectiveness of RISPERDAL CONSTA for the adjunctive maintenance treatment of bipolar I disorder was established in a multicenter, double-blind, placebo-controlled study of adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study.
Patients had to achieve stable remission for at least the last 4 weeks of an initial 16-week open label study period with RISPERDAL CONSTA as adjunctive therapy in addition to continuing their treatment as usual for their bipolar disorder, which consisted of mood stabilizers, antidepressants, and/or anxiolytics, before entering a 52-week double-blind, placebo-controlled adjunctive treatment study period. All oral antipsychotics were discontinued after the first three weeks of the initial RISPERDAL CONSTA injection. Time to relapse (recurrence) to a new mood episode, the primary endpoint, was delayed in patients receiving adjunctive therapy with RISPERDAL CONSTA as compared to placebo (p=0.01; log rank test). Over the course of the 52-week, double-blind relapse prevention phase, 23% of patients in the RISPERDAL CONSTA group and 46% of patients in the placebo group relapsed. RISPERDAL CONSTA was effective as adjunctive therapy in preventing recurrence of both manic and depressive mood episodes.
Pharmacodynamic effects: Clinical efficacy: Risperdal: Manic episodes in bipolar disorder: The efficacy of risperidone monotherapy in the acute treatment of manic episodes associated with bipolar I disorder was demonstrated in three double-blind, placebo-controlled monotherapy studies in approximately 820 patients who had bipolar I disorder, based on DSM-IV criteria. In the three studies, risperidone 1 to 6 mg/day (starting dose 3 mg in two studies and 2 mg in one study) was shown to be significantly superior to placebo on the pre-specified primary endpoint, i.e., the change from baseline in total Young Mania Rating Scale (YMRS) score at week 3. Secondary efficacy outcomes were generally consistent with the primary outcome. The percentage of patients with a decrease of ≥ 50% in total YMRS score from baseline to the 3-week endpoint was significantly higher for risperidone than for placebo. One of the three studies included a haloperidol arm and a 9-week double-blind maintenance phase. Efficacy was maintained throughout the 9-week maintenance treatment period. Change from baseline in total YMRS showed continued improvement and was comparable between risperidone and haloperidol at week 12.
The efficacy of risperidone in addition to mood stabilisers in the treatment of acute mania was demonstrated in one of two 3-week double-blind studies in approximately 300 patients who met the DSM-IV criteria for bipolar I disorder. In one 3-week study, risperidone 1 to 6 mg/day starting at 2 mg/day in addition to lithium or valproate was superior to lithium or valproate alone on the pre-specified primary endpoint, i.e., the change from baseline in YMRS total score at week 3. In a second 3-week study, risperidone 1 to 6 mg/day starting at 2 mg/day, combined with lithium, valproate, or carbamazepine was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this study was induction of risperidone and 9-hydroxy-risperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxy-risperidone. When the carbamazepine group was excluded in a post-hoc analysis, risperidone combined with lithium or valproate was superior to lithium or valproate alone in the reduction of YMRS total score.
Pharmacokinetics: Risperdal: RISPERDAL oral solution are bio-equivalent to RISPERDAL oral tablets.
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 CYP 2D6 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: 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%.
Pediatrics: The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children are similar to those in adults.
Risperdal Consta: General Characteristics of Risperidone After Administration of Risperdal Consta in Patients: After a single IM injection with Risperdal Consta, the release profile consists of a small initial release of drug (<1% of the dose), followed by a lag time of 3 weeks. The main release of drug starts from week 3 onwards, is maintained from 4 to 6 weeks, and subsides by week 7. Oral antipsychotic supplementation should therefore be given during the first 3 weeks of Risperdal Consta treatment (see Dosage & Administration).
After repeated intramuscular injections with 25 or 50 mg RISPERDAL CONSTA every two weeks, median trough and peak plasma concentrations of the active antipsychotic fraction fluctuated between 9.9-19.2 ng/ml and 17.9-45.5 ng/ml respectively.
The pharmacokinetics of risperidone are linear in the dose range of 25-50 mg injected every 2 weeks. No accumulation of risperidone was observed during long-term use (12 months) in patients who were injected with 25-50 mg every 2 weeks.
The previously mentioned studies were conducted with gluteal intramuscular injection. Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.
A single-dose study with oral risperidone 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%.
Pharmacokinetic/Pharmacodynamic Relationship: There was no relationship between the plasma concentrations of the active moiety and the change in total PANSS (Positive and Negative Syndrome Scale) and total ESRS (Extrapyramidal Symptom Rating Scale) scores across the assessment visits in any of the phase III trials where efficacy and safety was examined.
Absorption: The absorption of risperidone from RISPERDAL CONSTA is complete.
Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and alpha-1-acid glycoprotein. The plasma protein binding of risperidone is 90%, the active metabolite 9-hydroxy-risperidone is 77%.
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: The active antipsychotic fraction and risperidone clearances were 5.0 and 13.7 L/h in extensive metabolizers, respectively, and 3.2 and 3.3 L/h in poor metabolizers of CYP2D6, respectively.
The combination of the release profile and the dosage regimen (intramuscular injection every two weeks) result in sustained therapeutic plasma concentrations. Therapeutic plasma concentrations remain until 4 to 6 weeks after the last RISPERDAL CONSTA injection. The elimination phase is complete approximately 7 to 8 weeks after the last injection
Toxicology: Risperdal: Non-Clinical Information: 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.
Risperdal Consta: Animal Toxicology: Similar to the (sub)chronic toxicity studies with oral risperidone in rats and dogs, the major effects of treatment with RISPERDAL CONSTA (up to 12 months of intramuscular administration) were prolactin-mediated mammary gland stimulation, male and female genital tract changes, and central nervous system (CNS) effects, related to the pharmacodynamic activity of risperidone. In an oral toxicity study with juvenile rats, increased pup mortality and a delay in physical development was observed. In a 40-week study with juvenile dogs treated with oral risperidone, sexual maturation was delayed. Long bone growth was not affected at a dose similar to the maximum human oral 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 oral dose in adolescents.
RISPERDAL CONSTA administration to male and female rats for 12 and 24 months produced osteodystrophy at a dose of 40 mg/kg/2 weeks. The effect dose for osteodystrophy in rats was on a mg/m² basis 8 times the maximum recommended human dose and is associated with a plasma exposure 2 times the maximum anticipated exposure in humans at the maximum recommended dose. No osteodystrophy was observed in dogs treated for 12 months with RISPERDAL CONSTA up to 20 mg/kg/2 weeks. This dose yielded plasma exposures up to 14 times the maximum recommended human dose.
Carcinogenicity and Mutagenicity: There was no evidence of mutagenic potential.
As expected for a potent dopamine D₂-antagonist in an IM carcinogenicity study in Wistar (Hannover) rats (doses of 5 and 40 mg/kg every 2 weeks), prolactin-mediated increased incidences of endocrine pancreas, pituitary gland, and adrenal medullary neoplasia were observed at 40 mg/kg, while mammary gland neoplasia were present at 5 and 40 mg/kg. Hypercalcemia, postulated to contribute to an increased incidence of adrenal medullary tumors, was observed in both dose groups. There is no evidence to suggest that hypercalcemia might cause phaeochromocytomas in humans.
Renal tubular adenomas occurred in male rats at 40 mg/kg/2 weeks. No renal tumors occurred in the low dose, the NaCl 0.9%, or the microspheres vehicle control group. The mechanism underlying the renal tumors in RISPERDAL CONSTA treated male Winstar (Hannover) rats is unknown. A treatment-related increase in renal tumor incidence did not occur in the oral carcinogenicity studies with Wistar (Wiga) rats or in Swiss mice administered oral risperidone. Studies conducted to explore the substrain differences in the tumor organ profile suggest that the Wistar (Hannover) substrain employed in the carcinogenicity study differs substantially from the Wistar (Wiga) substrain employed in the oral carcinogenicity study with respect to spontaneous age-related non-neoplastic renal changes, serum prolactin increases, and renal changes in response to risperidone. There are no data suggesting kidney-related changes in dogs treated chronically with RISPERDAL CONSTA
The relevance of the osteodystrophy, the prolactin-mediated tumors and of the presumed rat substrain-specific renal tumors in terms of human risk is unknown.
Local irritation at the injection site in dogs and rats was observed after administration of high doses of RISPERDAL CONSTA. In a 24-month IM carcinogenicity study in rats, no increased incidence of injection site tumors was seen in either the vehicle or the active drug groups.

Risperdal: RISPERDAL TABLET (1MG & 2MG) AND RISPERDAL ORAL SOLUTION 1MG/ML: RISPERDAL 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. RISPERDAL alleviates affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia. RISPERDAL is also effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.
RISPERDAL is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorders.
RISPERDAL TABLETS (1MG) AND RISPERDAL ORAL SOLUTION 1MG/ML: RISPERDAL is indicated for the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from the age of 5 years and adolescents with subaverage intellectual functioning or mental retardation diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other disruptive behaviours require pharmacologic treatment. Pharmacological treatment should be an integral part of a more comprehensive treatment programme, including psychosocial and educational intervention. It is recommended that risperidone be prescribed by a specialist in child neurology and child and adolescent psychiatry or physicians well familiar with the treatment of conduct disorder of children and adolescents.
Risperdal Consta: RISPERDAL CONSTA is indicated for the treatment of schizophrenia and schizoaffective disorders.
RISPERDAL CONSTA is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder.

Risperdal: Schizophrenia: Switching from other antipsychotics: When medically appropriate, gradual discontinuation of the previous treatment while RISPERDAL therapy is initiated is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate RISPERDAL therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medications should be re-evaluated periodically.
Adults: RISPERDAL may be given once daily or twice daily.
Patients should start with 2 mg/day RISPERDAL. The dosage may be increased on the second day to 4 mg. From then on the dosage can be maintained unchanged, or further individualized, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.
Doses above 10 mg/day have not been shown to be superior in efficacy to lower doses and may cause extrapyramidal symptoms. Since the safety of doses above 16 mg/day has not been evaluated, doses above this level should not be used.
A benzodiazepine may be added to RISPERDAL when additional sedation is required.
Elderly (65 years of age and older): 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.
Children: 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: RISPERDAL should be administered on a once daily schedule, starting with 2 mg risperidone. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. Risperidone can be administered in flexible doses over a range of 1 to 6 mg per day to optimise each patient's level of efficacy and tolerability. Daily doses over 6 mg risperidone have not been investigated in patients with manic episodes.
As with all symptomatic treatments, the continued use of RISPERDAL must be evaluated and justified on an ongoing basis.
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. 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.
Conduct disorder: Children and adolescents from 5 to 18 years of age: For subjects ≥ 50 kg, a starting dose of 0.5 mg of oral solution 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 oral solution is the recommended pharmaceutical form to administer 0.5 mg. 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 of oral solution once daily is recommended. The oral solution is the recommended pharmaceutical form to administer 0.25 mg. 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 of oral solution once daily. The oral solution is the recommended pharmaceutical form to administer 0.75 mg.
As with all symptomatic treatments, the continued use of RISPERDAL must be evaluated and justified on an ongoing basis.
RISPERDAL 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.
Renal and hepatic impairment: Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than normal adults. 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.
RISPERDAL should be used with caution in these groups of patients.
Administration: RISPERDAL may be given as oral tablets or oral solution.
Risperdal Consta: For risperidone naive patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with RISPERIDAL CONSTA.
Schizophrenia and Schizoaffective Disorders: Dosage - Adults (older than 18 years of age): The recommended dose is 25 mg intramuscular every two weeks. Some patients may benefit from a higher doses of 37.5 mg or 50 mg. No additional benefit was observed with 75 mg in clinical trials in patients with schizophrenia. Doses higher than 50 mg every 2 weeks are not recommended.
Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see Pharmacology: Pharmacokinetics under Actions).
Upward dosage adjustment should not be made more frequently than every 4 weeks. The effect of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose.
Bipolar Disorder: The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder is 25 mg IM every 2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in this population. The physician who elects to use RISPERDAL CONSTA for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Special Populations: Pediatric (18 years of age and younger): RISPERDAL CONSTA has not been studied in children younger than 18 years.
Elderly (65 years of age and older): For elderly patients treated with RISPERDAL CONSTA, the recommended dosage is 25 mg IM every 2 weeks. Oral RISPERDAL (or another antipsychotic medication) should be given with the first injection of RISPERDAL CONSTA and should be continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site (see Pharmacology: Pharmacokinetics under Actions).
Hepatic and Renal Impairment: RISPERDAL CONSTA has not been studied in hepatically and renally impaired patients.
If hepatically or renally impaired patients require treatment with RISPERDAL CONSTA, a starting dose of 0.5 mg twice daily oral risperidone is recommended during the first week. The second week 1 mg twice daily or 2 mg once daily can be given. If an oral total daily dose of at least 2 mg is well tolerated, an injection of 25 mg RISPERDAL CONSTA can be administered every 2 weeks.
Administration: RISPERDAL CONSTA should be administered every two weeks by deep intramuscular deltoid or gluteal injection. Each injection should be administered by a health care professional using the appropriate enclosed safety needle. For deltoid administration, use the 1-inch needle alternating injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between the two buttocks. Do not administer intravenously (see Precautions and Administration and Instructions for Use and Handling and Disposal under Cautions for Usage).

Risperdal: Symptoms and signs: In general, reported signs and symptoms have been those resulting from an exaggeration of the drug's known pharmacological effects. 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 oral RISPERDAL and paroxetine.
In case of acute overdosage, the possibility of multiple drug involvement should be considered.
Treatment: Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to RISPERDAL. 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, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
Risperdal Consta: Overdosage is less likely to occur with parenteral than with oral medication, information pertaining to oral risperidone is presented.
Symptoms: In general, reported signs and symptoms have been those resulting from an exaggeration of Risperdal's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.
Overdosages of up to 360 mg have been reported. The available evidence suggests a wide safety margin. In overdose, rare cases of QT prolongation have been reported.
In case of acute overdosage, the possibility of multiple drug involvement should be considered.
Treatment: 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. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to Risperdal/Risperdal Consta. Therefore, appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures eg, IV fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

Risperdal: RISPERDAL is contraindicated in patients with a known hypersensitivity to the product.
Risperdal Consta: RISPERDAL CONSTA is contraindicated in patients with a known hypersensitivity to the product or any of the components.

Risperdal: Elderly patients with dementia: Overall mortality: Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including RISPERDAL. In placebo-controlled trials with RISPERDAL in this population, the incidence of mortality was 4.0% for RISPERDAL-treated patients compared to 3.1% for placebo-treated patients. The mean age (range) of patients who died was 86 years (range 67 - 100).
Concomitant use with furosemide: In the RISPERDAL 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.
No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. 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 higher incidence of cerebrovascular adverse events, (cerebrovascular accidents and transient ischemic attacks), including fatalities, in patients treated with RISPERDAL compared to patients receiving placebo (mean age 85 years; range 73 - 97).
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. RISPERDAL 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.
Leucopenia, neutropenia, and agranulocytosis: Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including RISPERDAL. Agranulocytosis has been reported very rarely (< 1/10000 patients) during post-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 RISPERDAL 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 RISPERDAL 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 RISPERDAL 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. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. Because RISPERDAL has a lower potential to induce extrapyramidal symptoms than classical neuroleptics, it should have a reduced risk of inducing tardive dyskinesia as compared to classical neuroleptics. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.
Extrapyramidal symptoms and psychostimulants: Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of one or both treatments should be considered (see Interactions).
Neuroleptic Malignant Syndrome (NMS): Neuroleptic Malignant Syndrome, characterized 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 RISPERDAL, should be discontinued.
Parkinson's Disease and Dementia with Lewy Bodies: Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including RISPERDAL, to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Hyperglycemia and diabetes mellitus: Hyperglycemia in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. 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. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related events in patients treated with the atypical antipsychotics, Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Weight gain: Significant weight gain has been reported. Monitoring weight gain is advisable when RISPERDAL is being used.
QT Interval: As with other antipsychotics, caution should be exercised when RISPERDAL 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 RISPERDAL during postmarketing surveillance (see Adverse Reactions).
Body temperature regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing RISPERDAL 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 medication with anticholinergic activity, or being subject to dehydration.
Antiemetic effect: An antiemetic 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.
Seizures: As with other antipsychotic drugs, RISPERDAL should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
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 RISPERDAL (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.
Other: See Schizophrenia: Elderly for specific posology recommendations for elderly patients under Dosage & Administration, Conduct and other disruptive behavior disorders for pediatric patients with conduct and other disruptive behavior disorders under Dosage & Administration, and Renal and Hepatic Impairment for patients with renal or hepatic impairment under Dosage & Administration.
Effects on Ability to Drive and Use Machines: RISPERDAL may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
Risperdal Consta: For risperidone-naive patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with Risperdal Consta.
Elderly Patients with Dementia: Overall Mortality: Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including Risperdal. In placebo-controlled trials with oral RSPERDAL in this population, the incidence of mortality was 4.0% for RISPERDAL-treated patients compared to 3.1% for placebo-treated patients. The mean age (range) of patients who died was 86 years (range 67-100).
Concomitant Use with Furosemide: In the oral RISPERDAL 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.
No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. 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 higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks,), including fatalities in patients (mean age 85 years; range 73-97) treated with oral RISPERDAL compared to patients receiving placebo.
Orthostatic Hypotension: Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during initiation of treatment. Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. Risperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease). The risk/benefit of further treatment with RISPERDAL CONSTA should be assessed if clinically relevant orthostatic hypotension persists.
Leukopenia, Neutropenia and Agranulocytosis: Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including RISPERDAL CONSTA. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-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 RISPERDAL CONSTA 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 RISPERDAL CONSTA and have their WBC followed until recovery.
Tardive Dyskinesia/Extrapyramidal Symptoms (TD/EPS): Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterized by rhythmic involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. Because risperidone has a lower potential to induce extrapyramidal symptoms than classical neuroleptics, it should have a reduced risk of inducing tardive dyskinesia as compared to classical neuroleptics. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.
Extrapyramidal symptoms and psychostimulants: Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of one or both treatments should be considered (see Interactions).
Neuroleptic Malignant Syndrome (NMS): Neuroleptic Malignant Syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur in association with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all antipsychotic drugs, including risperidone, should be discontinued. After the last administration of RISPERDAL CONSTA, plasma levels of risperidone are present for up to (a minimum) of 6 weeks.
Parkinson's Disease and Dementia with Lewy Bodies: Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including RISPERDAL CONSTA, to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
Hypersensitivity Reactions: Although tolerability with oral risperidone should be established prior to initiating treatment with RISPERDAL CONSTA, very rare cases of anaphylactic reaction have been reported during postmarketing experience in patients who have previously tolerated oral risperidone. (see Dosage & Administration and Adverse Reactions).
If hypersensitivity reactions occur, discontinue use of RISPERDAL CONSTA; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve. (see Contraindications and Adverse Reactions).
Hyperglycemia and Diabetes Mellitus: Hyperglycemia in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. 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. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Weight Gain: Significant weight gain has been reported. Monitoring weight gain is advisable when RISPERDAL CONSTA is being used.
QT Interval: As with other antipsychotics, caution should be exercised when RISPERDAL CONSTA 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 RISPERDAL during postmarketing surveillance (see Adverse Reactions).
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing RISPERDAL CONSTA 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 medication with anticholinergic activity, or being subject to dehydration.
Antiemetic Effect: An antiemetic 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.
Seizures: As with other antipsychotic drugs, RISPERDAL CONSTA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
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 RISPERDAL CONSTA (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.
Administration: Care must be taken to avoid inadvertent injection of RISPERDAL CONSTA into a blood vessel (see Adverse Reactions - retinal artery occlusion).
Effects on the Ability to Drive or Operate Machinery: Risperidone may interfere with the activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

Pregnancy: The safety of risperidone for use during human pregnancy has not been established.
A retrospective observational cohort study based on a US claims database compared the risk of congenital malformations for live births among women with and without antipsychotic use during the first trimester of pregnancy. The risk of congenital malformations with risperidone, after adjusting for confounder variables available in the database, was elevated compared to no antipsychotic exposure (relative risk=1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain these findings and teratogenic effects have not been observed in non-clinical studies. Based on the findings of this single observational study, a causal relationship between in utero exposure to risperidone and congenital malformations has not been established.
Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed.
Neonates exposed to antipsychotic drugs (including RISPERDAL) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while is some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
RISPERDAL/RISPERDAL CONSTA should only be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breast-feeding: In animal studies, risperidone and 9-hydroxy-risperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxy-risperidone are also excreted in human breast milk. Therefore, women receiving RISPERDAL 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 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:Risperdal: The safety of RISPERDAL was evaluated from a clinical trial database consisting of 9803 patients exposed to one or more doses of RISPERDAL for the treatment of various psychiatric disorders in adults, elderly patients with dementia, and pediatrics. Of these 9803 patients, 2687 were patients who received RISPERDAL while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL 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 RISPERDAL-treated adult patients in nine 3- to 8-week double-blind, placebo-controlled trials are shown in Table 1. (See Table 1.)

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

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

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Risperdal Consta: The safety of RISPERDAL CONSTA was evaluated from a clinical trial database consisting of 2392 patients exposed to one or more doses of RISPERDAL CONSTA for the treatment of schizophrenia. Of these 2392 patients, 332 were patients who received RISPERDAL CONSTA while participating in a 12-week double-blind, placebo-controlled trial. A total of 202 of the 332 were schizophrenic patients who received 25 mg or 50 mg RISPERDAL CONSTA. The conditions and duration of treatment with RISPERDAL CONSTA in the other clinical trials 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 4 years) exposures. In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as adjunctive maintenance treatment in patients with bipolar disorder and when administered as monotherapy for the treatment of bipolar I disorder.
In the monotherapy study for the maintenance treatment of bipolar I disorder, the subjects in this multicenter, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or long-acting injection), were stable on other antipsychotics or mood stabilizers, or were experiencing an acute episode. After a 3-week period of treatment with open-label oral risperidone (n=440), subjects who demonstrated an initial response to oral risperidone in this period and those who were stable on risperidone (oral or long-acting injection) at study entry entered into a 26-week stabilization period of open-label RISPERDAL CONSTA (n=501). Subjects who demonstrated a maintained response during this period were then randomized into a 24-month double-blind, placebo-controlled period in which they received RISPERDAL CONSTA (n=154) or placebo (n=149) as monotherapy. Subjects who relapsed or who completed the double-blind period could choose to enter an 8-week open-label RISPERDAL CONSTA extension period (n=160).
In the adjunctive maintenance treatment study involving patients with bipolar disorder, the subjects in this multicenter, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I or II and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study. At the start of this study, all patients (n=275) entered into a 16-week open-label treatment phase in which they received RISPERDAL CONSTA in addition to continuing their treatment as usual, which consisted of various mood stabilizers, antidepressants, and/or anxiolytics. Patients who reached remission at the end of this 16-week open-label treatment phase (n=139) were then randomized into a 52-week double-blind, placebo-controlled phase in which they received RISPERDAL CONSTA (n=72) or placebo (n=67) as adjunctive treatment in addition to continuing their treatment as usual. Patients who did not reach remission at the end of the 16-week open-label treatment phase could choose to continue to receive RISPERDAL CONSTA as adjunctive therapy in an open-label manner, in addition to continuing their treatment as usual, for up to an additional 36 weeks as clinically indicated for a total period of up to 52 weeks; these patients (n=70) were also included in the evaluation of safety.
The majority of all adverse reactions were mild to moderate in severity.
Double-Blind, Placebo-Controlled Data - Schizophrenia: Adverse reactions reported by ≥ 2% of RISPERDAL CONSTA- treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial are shown in Table 4. (See Table 4.)

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Double-Blind, Placebo-Controlled Data - Bipolar Disorder: Table 5 lists the treatment-emergent adverse reactions reported in 2% or more of RISPERDAL CONSTA-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. (See Table 5.)

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Table 6 lists the treatment-emergent adverse reactions reported in ≥ 4% of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as adjunctive maintenance treatment in patients with bipolar disorder. (See Table 6.)

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Other clinical trial data: Risperdal: 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. This subsection includes additional adverse reactions reported with risperidone and/or paliperidone in clinical trials. Adverse reactions reported with risperidone and/or paliperidone by ≥ 1% of RISPERDAL-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 by < 1% of RISPERDAL-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 paediatric patients) are shown in Table 8. (See Table 8.)

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Adverse reactions reported with risperidone and/or paliperidone in other clinical trials but not reported by RISPERDAL-treated subjects in a pooled dataset of 23 double-blind, placebo-controlled pivotal studies are shown in Table 9. (See Table 9.)

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Risperdal Consta: 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. This subsection includes additional adverse reactions reported with risperidone and/or paliperidone in clinical trials. Adverse reactions reported with risperidone and/or paliperidone by ≥ 2% of RISPERDAL CONSTA-treated subjects with schizophrenia are shown in Table 10. (See Table 10.)

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Adverse reactions reported with risperidone and/or paliperidone by < 2% of RISPERDAL CONSTA-treated subjects with schizophrenia are shown in Table 11. (See Table 11.)

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Adverse reactions reported with risperidone and/or paliperidone in other clinical trials but not reported by RISPERDAL CONSTA (25 mg or 50 mg)-treated subjects with schizophrenia are shown in Table 12. (See Table 12.)

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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 13 and 14. In the table, the frequencies are provided according to the following convention: Very common: ≥ 1/10; Common: ≥ 1/100 to < 1/10; Uncommon: ≥ 1/1,000 to < 1/100; Rare: ≥ 1/10,000 to < 1/1,000; Very rare: < 1/10,000, including isolated reports; Unknown: Cannot be estimated from the available data.
In Tables 13 and 14, adverse reactions are presented by frequency category based on incidence in clinical trials, when known.
Risperdal: (See Table 13.)

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Risperdal Consta: (See Table 14.)

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Very rarely, cases of anaphylactic reaction after injection with RISPERDAL CONSTA have been reported during postmarketing experience in patients who have previously tolerated oral risperidone.

Risperdal: Pharmacodynamic-related interactions: Centrally-acting drugs and alcohol: Given the primary CNS effects of RISPERDAL, it should be used with caution in combination with other centrally acting drugs or alcohol.
Levodopa and dopamine agonists: RISPERDAL may antagonize the effect of levodopa and other dopamine agonists.
Psychostimulants: The combined use of psychostimulants (e.g. methylphenidate) with risperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see Precautions).
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 RISPERDAL with drugs known to prolong the QT interval.
Pharmacokinetic-related interactions:; Risperidone is mainly metabolized through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxy-risperidone 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.
Risperdal: Food does not affect the absorption of RISPERDAL.
Strong CYP2D6 inhibitors: Co-administration of RISPERDAL 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 RISPERDAL.
CYP3A4 and/or P-gp inhibitors: Coadministration of RISPERDAL 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 RISPERDAL.
CYP3A4 and/or P-gp inducers: Co-administration of RISPERDAL 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 RISPERDAL.
Highly protein-bound drugs: When RISPERDAL is taken together with 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.
Examples: Examples of drugs that may potentially interact or that were shown not to interact with risperidone are listed below: Antibacterials: Erythromycin, a moderate 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 a P-gp inducer, has been shown to decrease the plasma concentrations 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.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate.
Antifungals: Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.
Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxy-risperidone.
Antipsychotics: Phenothiazines, may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Aripiprazole, a CYP2D6 and CYP3A4 substrate: Risperidone tablets or injections did not affect 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 20 mg/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. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.
Risperdal: Pediatric population: Interaction studies have only been performed in adults. The relevance of the results from these studies in pediatric patients is unknown.

Risperdal: Incompatibilities: RISPERDAL tablets: none.
RISPERDAL oral solution: incompatible with tea.
RISPERDAL CONSTA: RISPERDAL CONSTA cannot be mixed or diluted with drugs or fluids other than the supplied diluent for administration.
Instructions For Use/Handling: Oral Solution: 1: The bottle comes with a child-resistant cap, and should be opened as follows: Push the plastic screw cap down while turning it counter clockwise.
Remove the unscrewed cap.
2: Insert the pipette into the bottle.
3: While holding the bottom ring, pull the top ring up to the mark that corresponds to the number of milliliters or milligrams you need to give.
4: Holding the bottom ring, remove the entire pipette from the bottle. Empty the pipette into any non-alcoholic drink, except for tea, by sliding the upper ring down. Close the bottle. Rinse the pipette with some water.
Risperdal Consta: After Reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hrs at 25°C. From a microbiological point of view, Risperdal Consta should be used immediately. If not used immediately, the in-use storage time and conditions prior to use are the responsibility of the user and would normally not be longer than 6 hrs at 25°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
Incompatibilities: Risperdal Consta cannot be mixed or diluted with drugs or fluids other than the supplied diluent for administration.

Risperdal: RISPERDAL oral tablets should be stored below 30°C.
RISPERDAL oral solution should be stored below 30°C and should be protected from freezing.
Risperdal Consta: The entire dose pack should be stored in the refrigerator (2 - 8°C) and protected from light. It should not be exposed to temperatures above 25°C.
If refrigeration is unavailable, RISPERDAL CONSTA can be stored at temperatures not exceeding 25°C for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C.
Shelf Life: RISPERDAL oral tablets: 3 years.
RISPERDAL oral solution: 3 years when protected from freezing.
Opened container: 3 months when protected from freezing.
RISPERDAL CONSTA: 36 months at 2-8°C.
After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 6 hours at 25°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Antipsychotics

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

B