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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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Click on icon to see table/diagram/imageMaintenance 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.
