Risperdal/Risperdal Consta

Risperdal/Risperdal Consta

risperidone

Manufacturer:

Johnson & Johnson
Full Prescribing Info
Contents
Risperidone.
Description
Risperdal: The oral solution contains 1 mg/mL risperidone.
Risperdal Consta: RISPERDAL CONSTA contains 25 mg, 37.5 mg or 50 mg risperidone. RISPERDAL CONSTA is an extended release microspheres formulation of risperidone, composed of risperidone drug substance micro encapsulated in polylactide-co-glycolide, at a concentration of 381 mg risperidone per gram of microspheres.
Prolonged-release powder and diluent for suspension for injection.
Excipients/Inactive Ingredients: Risperdal: Tartaric acid; Benzoic acid; Sodium hydroxide; Purified water.
Risperdal Consta: RISPERDAL CONSTA Extended Release Microspheres 7525 DL JN1 [poly-(d,l-lactide-co-glycolide)] polymer.
Diluent: carmellose sodium 40mPa.s, citric acid anhydrous, disodium hydrogen phosphate dihydrate, polysorbate 20, sodium chloride, sodium hydroxide, water for injection.
Action
Pharmacotherapeutic group: Other antipsychotics. ATC code: N05AX08.
Pharmacology: Pharmacodynamics: 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, 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 extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Risperdal Consta: Further information on clinical trials: Schizophrenia: The effectiveness of RISPERDAL CONSTA (25 mg and 50 mg) in the management of the 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 Figure 1 and Figure 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 had, on average, more manic episodes than depressive episode.
Bipolar I Disorder - Adjunctive Therapy: The effectiveness of RISPERDAL CONSTA as an adjunct to treatment with lithium or valproate for the maintenance treatment of Bipolar Disorder was established in a multi-center, randomized, 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.
A total of 240 patients were treated during a 16-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), as adjunctive therapy in addition to continuing their treatment as usual for their bipolar disorder, which consisted of mood stabilizers (primarily lithium and valproate), antidepressants, and/or anxiolytics. All oral antipsychotics were discontinued after the first three weeks of the initial RISPERDAL CONSTA injection. In the open-label phase, 124 (51.7%) were judged to be stable for at least 4 weeks and were randomized to double-blind treatment with either the same dose of RISPERDAL CONSTA or placebo in addition to continuing their treatment as usual and monitored for relapse during a 52-week period. The primary endpoint was time to relapse to any new mood episode (depression, mania, hypomania, or mixed).
Time to relapse was delayed in patients receiving adjunctive therapy with RISPERDAL CONSTA as compared to placebo. The relapse types were about half depressive and half manic or mixed episodes.
Pharmacokinetics: Risperdal: RISPERDAL oro-dispersible tablets and 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 proportionally: 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%.
Risperdal Consta: General characteristics of risperidone after administration of RISPERDAL CONSTA in patients: After a single intramuscular 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 two weeks.
The above 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 antipsychotic fraction 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 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: 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 CYP 2D6, 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.
Special Population: Elderly: In an open-label trial with RISPERDAL CONSTA, steady-state concentrations of risperidone plus 9-hydroxy-risperidone in elderly patients treated up to 12 months fell within the range of values observed in non-elderly patients.
Renal Impairment: In patients with moderate to severe renal disease treated with oral RISPERDAL, clearance of risperidone plus 9-hydroxy-risperidone was decreased by 60%, compared with young healthy subjects. Although patients with renal impairment were not studied with RISPERDAL CONSTA, it is recommended that patients with renal impairment be carefully titrated on oral RISPERDAL before treatment with RISPERDAL CONSTA is initiated.
Hepatic Impairment: Whereas the pharmacokinetics of oral RISPERDAL in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Although patients with hepatic impairment were not studied with RISPERDAL CONSTA, it is recommended that patients with hepatic impairment be carefully titrated on oral RISPERDAL before treatment with RISPERDAL CONSTA is initiated.
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: Non-clinical Information: 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 intramuscular carcinogenicity study in Wistar (Hannover) rats (doses of 5 and 40-mg/kg/2 weeks), prolactin-mediated increased incidences of endocrine pancreas, pituitary gland, and adrenal medullary tumors were observed at 40-mg/kg, while mammary gland tumors 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 Wistar (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 osteodystropy, 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 active drug groups.
Indications/Uses
Risperdal: 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 indicated for 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 judgement including disruptive or aggressive behaviors.
Risperdal is indicated for the treatment (up to 12 weeks) of agitation, aggression or psychotic symptoms in patients with moderate to severe dementia of the Alzheimer type.
Risperdal is indicated in the treatment of conduct and other disruptive behavior disorders where aggressive or other disruptive behaviors (e.g., impulsivity and self-injurious behaviors) are prominent. The physician who elects to use Risperdal for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Risperdal may improve adaptive skills in children with autistic disorder accompanied by serious behavioral problems such as aggression tantrums and self-injurious behavior.
Risperdal Consta: RISPERDAL CONSTA is indicated for the treatment of schizophrenia and schizoaffective disorder.
RISPERDAL CONSTA is indicated as monotherapy for the maintenance treatment of bipolar I disorder to delay occurrence of mood episodes (see section Pharmacology: Pharmacodynamics: Prevention of Mood Episodes in Bipolar I Disorder - Monotherapy under Actions).
RISPERDAL CONSTA is indicated for adjunctive maintenance treatment of bipolar I disorder to delay occurrence of mood episodes. (see Pharmacology: Pharmacodynamics: Bipolar I Disorder - Adjunctive Therapy under Actions).
Dosage/Direction for Use
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 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.
Special populations: Pediatrics (13-17 years of age): A starting dose of 0.5 mg daily is recommended, administered as a single-daily dose either in the morning or evening. If indicated, this dosage can then be adjusted at intervals not less than 24 hours in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day. Efficacy has been demonstrated at doses between 1 and 6 mg/day. Doses higher than 6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
Experience in schizophrenia is lacking in children less than 13 years of age.
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.
Bipolar mania: Adults: Risperdal 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. Efficacy was demonstrated in flexible doses over a range of 1 to 6 mg per day.As with all symptomatic treatments, the continued use of Risperdal® must be evaluated and justified on an ongoing basis.Special populationsPediatrics (10-17 years of age)A starting dose of 0.5 mg once daily is recommended, administered as a single-daily dose in either the morning or evening. If indicated, this dosage can then be adjusted at intervals not less than 24 hours in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Efficacy has been demonstrated at doses between 0.5 and 6 mg/day. Doses higher than 6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
As with all symptomatic treatments, the continued use of Risperdal must be evaluated and justified on an ongoing basis.
Experience is lacking in bipolar mania in children less than 10 years of age.
Agitation, aggression or psychotic symptoms in patients with dementia of the Alzheimer type: 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.
Once patients have reached their target dose, a once daily dosing regimen can be considered. As with all symptomatic treatments, the continued use of Risperdal must be evaluated and justified on an ongoing basis.
Conduct and other disruptive behavior disorders (5-18 years of age): Subject ≥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.
Subject <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 Risperdal must be evaluated and justified on an ongoing basis.
Experience is lacking in children aged less than 5 years of age.
Autism: Pediatrics (5-17 years of age): The dosage of Risperdal 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 0.25 mg/day were not effective in clinical studies. (See Table 1.)


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Risperdal can be administered once daily (QD) or twice daily (BID).
Patients experiencing somnolence may benefit from a switch in dosing from once daily (QD) to either once daily at bedtime (qHS) or twice daily (BID).
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 aged less than 5 years of age.
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.
Risperdal Consta: For patients who have never taken oral risperidone, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with RISPERDAL CONSTA.
Adults (older than 18 years of age): Schizophrenia: The recommended dose for the treatment of schizophrenia is 25 mg intramuscularly every two weeks. Some patients may benefit from the higher doses of 37.5 mg or 50 mg. No additional benefit was observed with 75 mg in clinical trials in patients with schizophrenia.
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 intramuscularly every two weeks. Some patients may benefit from the higher doses of 37.5 mg or 50 mg. Doses above 50 mg were not studied in patients with bipolar disorder. 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 section Pharmacodynamics: 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.
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): The recommended dose is 25 mg intramuscular every two weeks. Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see Pharmacodynamics: Pharmacokinetics under Actions).
RISPERDAL is well tolerated by the elderly.
Hepatic and renal impairment: RISPERDAL CONSTA has not been studied in hepatically and renally impaired patients and should therefore be used with caution.
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 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 using the enclosed appropriate 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. Prior to each administration, the site of injection should be examined for any signs of inflammation. If such signs exist, an alternative site should be chosen for injection. Do not administer intravenously (see Administration under Precautions and Instructions for use and Handling and Disposal under Cautions for usage).
This product does not contain an antimicrobial agent. It is for single use in one patient only. Any residue is to be discarded.
Overdosage
While overdosage is less likely to occur with parenteral than with oral medication, information pertaining to oral risperidone is presented.
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. 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: Administration of activated charcoal together with a laxative should be considered.
Contraindications
RISPERDAL/RISPERDAL CONSTA is contraindicated in patients with a known hypersensitivity to the product or any of the components.
Special Precautions
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/RISPERDAL CONSTA. 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/RISPERDAL CONSTA 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/RISPERDAL CONSTA 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/RISPERDAL CONSTA 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 anti psychotic agents , including RISPERDAL/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 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/RISPERDAL CONSTA 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/RISPERDAL CONSTA 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 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.
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/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/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.
Hyperglycemia and diabetes mellitus: Hyperglycemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported during treatment with RISPERDAL. 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 RISPERDAL/RISPERDAL CONSTA should be monitored for symptoms of hyperglycemia and diabetes mellitus. (see Adverse Reactions).
Weight gain: Significant weight gain has been reported. Monitoring weight gain is advisable when RISPERDAL/RISPERDAL CONSTA is being used. QT Interval.
As with other antipsychotics, caution should be exercised when RISPERDAL/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/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/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/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/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.
Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy.
Effects on Ability to Drive and Use Machines: Risperidone 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: See Schizophrenia for specific posology recommendations under Dosage & Administration for elderly patients, Behavioral Disturbances in Patients With Dementia under Dosage & Administration for elderly patients with dementia, Bipolar Mania under Dosage & Administration for patients with bipolar mania, Conduct and Other Disruptive Behavior Disorders under Dosage & Administration for pediatric patients with conduct and other disruptive disorders, Autism under Dosage & Administration for pediatric patients with autism, Renal and Hepatic Impairment under Dosage & Administration for patients with renal or hepatic impairment.
Risperdal Consta: For risperidone naive patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with RISPERDAL CONSTA.
Venous thromboembolism: As with other antipsychotics, caution is advised when prescribing with medications known to prolong the QT interval.
If further sedation is required, an additional drug (such as benzodiazepine) should be administered rather than increasing the dose of RISPERDAL CONSTA.
As with other antipsychotics, patients should be advised of the potential for weight gain.
Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.
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).
Administration: Care must be taken to avoid inadvertent injection of RISPERDAL CONSTA into a blood vessel (see Retinal artery occlusion under Adverse Reactions).
Use In Pregnancy & Lactation
Pregnancy: The safety of RISPERDAL/RISPERDAL CONSTA 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/RISPERDAL CONSTA) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in the neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder.
RISPERDAL/RISPERDAL CONSTA should only be used during pregnancy if the benefits outweigh the risks.
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/RISPERDAL CONSTA should not breast-feed.
Adverse Reactions
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 practices.
Risperdal: Clinical trial data: 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 drug reactions (ADRs) reported by ≥1% of RISPERDAL-treated adult patients in nine 3- to 8-week double-blind, placebo¬≠ controlled trials are shown in Table 2. (See Table 2.)


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Double-blind, placebo-controlled data - Elderly patients with dementia: Adverse drug reactions (ADRs) 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 3. Table 3 includes only those ADRs that are either not listed in Table 2 or those ADRs that occurred at ≥2 times the frequency of the ADRs listed in Table 2. (See Table 3.)


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Double-blind, placebo-controlled data - Pediatric patients: Adverse drug reactions (ADRs) reported by ≥1% of RISPERDAL-treated pediatric patients in eight 3- to 8-week double-blind, placebo-controlled trials are shown in Table 4. Table 4 includes only those ADRs that are either not listed in Table 2 or those ADRs that occurred at ≥2 times the frequency of the ADRs listed in Table 2. (See Table 4.)


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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. This subsection includes additional ADRs reported with risperidone and/or paliperidone in clinical trials. ADRs 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 5. (See Table 5.)


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ADRs 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 6. (See Table 6.)


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ADRs 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 7. (See Table 7.)


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Postmarketing Data: Adverse events first identified as ADRs during postmarketing experience with risperidone and/or paliperidone are included in Table 8. In the table, the frequencies are provided according to the following convention: Very common: ≥1/10; Common: ≥1/100 and <1/10; Uncommon: ≥1/1,000 and <1/100; Rare: ≥1/10,000 and <1/1,000; Very rare: <1/10,000, including isolated reports; Unknown: Cannot be estimated from the available data.
In Table 8, ADRs are presented by frequency category based on spontaneous reporting rates. (See Table 8.)


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Risperdal Consta: Clinical Trial Data: 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 monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in this multi-center, 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).
Safety data are also presented from a trial assessing the efficacy and safety of RISPERDAL CONSTA when administered as adjunctive maintenance treatment in patients with bipolar disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I or Type 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 (primarily lithium and valproate), 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.
Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reaction was reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of RISPERDAL CONSTA (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A casual association for RISPERDAL CONSTA often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reactions 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.
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 trials are shown in Table 9. (See Table 9.)


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Double-Blind, Placebo-Controlled Data - Bipolar Disorder: Table 10 lists the treatment-emergent ADRs 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 10.)


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Table 11 lists the treatment-emergent ADRs 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 11.)


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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. 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 12. (See Table 12.)


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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 13. (See Table 13.)


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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 14. (See Table 14.)


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Postmarketing Data: Adverse events first identified as adverse reactions during postmarketing experience with risperidone and/or paliperidone are included in Table 15. In the table, the frequencies are provided according to the following convention: Very common: ≥1/10; Common: ≥1/100 and <1/10; Uncommon: ≥1/1,000 and <1/100; Rare: ≥1/10,000 and <1/1,000; Very rare: <1/10,000, including isolated reports; Unknown: Cannot be estimated from the available data.
In Table 15, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 15.)


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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.
Drug Interactions
The interactions of RISPERDAL CONSTA with co-administration of other drugs have not been systematically evaluated. The drug interaction data provided in this section are based on studies with oral RISPERDAL.
Pharmacodynamic-related interactions: Centrally-acting drugs and alcohol: Given the primary CNS effects of RISPERDAL/RISPERDAL CONSTA, it should be used with caution in combination with other centrally acting drugs or alcohol.
Levodopa and dopamine agonists: RISPERDAL/RISPERDAL CONSTA 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 rispelidone and antihypertensive treatment.
Drugs known to prolong the QT interval: Caution is advised when prescribing RISPERDAL/RISPERDAL CONSTA 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 anti psychotic fraction.
Risperdal: Food does not affect the absorption of RISPERDAL.
Strong CYP2D6 inhibitors: Co-administration of RISPERDAL/RISPERDAL CONSTA 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/RISPERDAL CONSTA.
CYP3A4 and/or P-gp inhibitors: Coadministration of RISPERDAL/RISPERDAL CONSTA 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/RISPERDAL CONSTA.
CYP3A4 and/or P-gp inducers: Coadministration of RISPERDAL/RISPERDAL CONSTA 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 or discontinued, the physician should re-evaluate the dosing of RISPERDAL/RISPERDAL CONSTA.
Highly protein-bound drugs: When RISPERDAL/RISPERDAL CONSTA 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 drug that may potentially interact or that were shown not to interact with risperidone are listed as follows: Antibacterials: Erythromycin, a moderate CYP 3A4 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 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.
RISPERDAL/RISPERDAL CONSTA 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 anti psychotic 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.
Aririprazole, 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 anti psychotic fraction.
Beta-Blockers: Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active anti psychotic 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 anti psychotic fraction.
Digitalis Glycosides: RISPERDAL/RISPERDAL CONSTA 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: Risperdal: H2-receptor antagonists: Cimetidine and ranitidine, both weak inhibitors of CYP2D6 increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.
Risperdal Consta: 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: RISPERDAL/RISPERDAL CONSTA 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 anti psychotic fraction.
Paroxetine, a strong CYP2D6 inhibitors, increase the plasma concentration 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 rispetidone active anti psychotic fraction.
Triciclyc 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 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.
Caution For Usage
Instructions For Use/Handling: Risperdal: 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.
Insert the pipette into the bottle.
While holding the bottom ring, pull the top ring up to the mark that corresponds to the number of milliliters or milligrams needed to give.
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: RISPERDAL CONSTA requires close attention to these step-by-step Instructions for Use to help ensure successful administration.
Wait 30 minutes: Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting.
Do not warm any other way.
Use components provided: The components in this dose pack are specifically designed for use with RISPERDAL CONSTA. RISPERDAL CONSTA must be reconstituted only in the diluent supplied in the dose pack.
Do not substitute ANY components of the dose pack.
Do not store suspension after reconstitution: Administer dose as soon as possible after reconstitution to avoid settling.
Proper dosing: The entire contents of the vial must be administered to ensure intended dose of RISPERDAL CONSTA is delivered.
Single-use device.
Do not reuse. Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to re-process the device for subsequent re-use may adversely affect the integrity of the device or lead to deterioration in performance.
Step 1: Assemble components. Connect vial adapter to vial.
Remove cap from vial: Flip off colored cap from vial. Wipe top of the grey stopper with an alcohol swab. Allow to air dry. Do not remove grey rubber stopper.
Prepare vial adapter: Hold sterile blister. Peel back and remove paper backing. Do not remove vial adapter form blister. Do not touch spike tip at any time. This will result in contamination.
Connect vial adapter to vial: Place vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial.
Connect prefilled syringe to vial adapter. Remove sterile blister: Remove vial adaptor from sterile blister only when the patient is ready to remove the white cap from the prefilled syringe. Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove. Do not shake. Do not touch exposed luer opening on vial adapter. This will result in contamination.
Use proper grip: Hold by white collar at the tip of the syringe. Do not hold syringe by the glass barrel during assembly.
Remove cap: Holding the white collar, snap off the white cap. Do not twist or cut off the white cap. Do not touch the syringe tip. This will result in contamination. The broken-off cap can be discarded.
Connect syringe to vial adapter: Hold vial adapter by skirt to keep stationary. Hold syringe by white collar then insert tip into the luer opening of the vial adpater. Do not hold the glass syringe barrel. This may cause the white collar to loosen or detach. Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug. Do not over-tighten. Over-tightening may cause the syringe tip to break.
Step 2: Reconstitute microspheres.
Inject diluent: Inject entire amount of diluent from syringe into the vial. VIal contents will now be under pressure. Keep holding the plunger rod down with thumb.
Suspend microspheres in diluent: Continuing to hold down the plunger rod, shake vigorously for at least 10 seconds. Check the suspension. When properly mixed, the suspension appears uniform, thick and milky in color. Microspheres will be visible in the liquid. Immediately proceed to the next step so suspension does not settle.
Transfer suspension to syringe: Invert vial completely. Slowly pull plunger rod down to withdraw the entire contents from the vial into the syringe.
Remove vial adapter: Hold white collar on the syringe and unscrew from the vial adapter. Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. Discard both vial and vial adapter appropriately.
Step 3: Attach needle.
Select appropriate needle: Choose needle based on injection location (gluteal or deltoid).
Attach needle: Peel blister pouch open part way and use to grasp the base of the needle. Holding the white collar on the syringe, attach syringe to needle luer connection with a firm clockwise twisting motion until snug. Do not touch needle luer opening. This will result in contamination.
Resuspend microspheres: Fully remove the blister pouch. Just before injection, shake syringe vigorously again, as some setting will have occurred.
Step 4: Inject dose.
Remove transparent needle protector: Move the needle safety device back towards the syringe. Then hold white collar on syringe and carefully pull the transparent needle protector straight off. Do not twist transparent needle protector, as the luer connection may loosen.
Remove air bubbles: Hold needle upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air.
Inject: Immediately inject entire contents of syringe intamuscularly (IM) into the gluteal or deltoid muscle of the patient. Gluteal injection should be make into the upper-outer quadrant of the gluteal area. Do not administer intravenously.
Secure needle in safety device: Using one hand, place needle safety device at a 45 degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device.
Avoid needle stick injury: Do not use two hands. Do not intentionally disengage or mishandle the needle safety device. Do not attempt to straighten the needle or engage the safety device if the needle is bent or damaged.
Properly dispose of needles: Check to confirm needle safety device is fully engaged. Discard in an approved sharps container. Also discard the unused needle provided in the dose pack.
Incompatibilities: Risperdal: 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.
Storage
Risperdal: Risperdal should be stored at 30°C or below 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 not more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C.
Shelf-Life: Risperdal: 36 months.
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.
MIMS Class
Antipsychotics
ATC Classification
N05AX08 - risperidone ; Belongs to the class of other antipsychotics.
Presentation/Packing
Form
Risperdal Consta inj 25 mg
Packing/Price
(+ diluent) 1's (Rp950,250/vial)
Form
Risperdal Consta inj 37.5 mg
Packing/Price
(+ diluent) 1's (Rp950,250/vial)
Form
Risperdal Consta inj 50 mg
Packing/Price
(+ diluent) 1's (Rp1,050,000/vial)
Form
Risperdal oral soln 1 mg/mL
Packing/Price
30 mL x 1's (Rp375,375/botol)
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