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Mechanism of Action
The mechanism of action of RISPERDAL® CONSTA®, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations > 10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
The clinical effect from RISPERDAL® CONSTA® results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of RISPERDAL® CONSTA®.
After a single intramuscular (gluteal) injection of RISPERDAL® CONSTA®, there is a small initial release of the drug ( < 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) injection. Therefore, oral antipsychotic supplementation should be given during the first 3 weeks of treatment with RISPERDAL® CONSTA® to maintain therapeutic levels until the main release of risperidone from the injection site has begun [see DOSAGE AND ADMINISTRATION]. Following single doses of RISPERDAL® CONSTA®, the pharmacokinetics of risperidone, 9-hydroxyrisperidone (the major metabolite), and risperidone plus 9-hydroxyrisperidone were linear in the dosing range of 12.5 mg to 50 mg.
The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of RISPERDAL® CONSTA® results in sustained therapeutic concentrations. Steady-state plasma concentrations are reached after 4 injections and are maintained for 4 to 6 weeks after the last injection. Following multiple doses of 25 mg and 50 mg RISPERDAL® CONSTA®, plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone were linear.
Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.
Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.
The interactions of RISPERDAL® CONSTA® with coadministration of other drugs have not been systematically evaluated in human subjects. Drug interactions are based primarily on experience with oral RISPERDAL®. Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9hydroxyrisperidone [see DRUG INTERACTIONS]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of RISPERDAL® in patients receiving quinidine have not been evaluated, but observations in a modest number (n≅70) of poor metabolizers given oral RISPERDAL® do not suggest important differences between poor and extensive metabolizers. Second, co-administration of carbamazepine and other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with oral RISPERDAL® cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see DRUG INTERACTIONS]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see DRUG INTERACTIONS].
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone plus 9-hydroxyrisperidone following RISPERDAL® CONSTA®administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of risperidone. The clearance of risperidone and risperidone plus 9hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No accumulation of risperidone was observed during long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or 50 mg RISPERDAL® CONSTA®. The elimination phase is complete approximately 7 to 8 weeks after the last injection.
In patients with moderate to severe renal disease treated with oral RISPERDAL®, clearance of the sum of risperidone and its active metabolite 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 at a dose of 25 mg. A lower initial dose of 12. 5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal impairment [see DOSAGE AND ADMINISTRATION].
While 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 α1acid 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 at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic impairment [see DOSAGE AND ADMINISTRATION].
In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone in otherwise healthy elderly patients ( ≥ 65 years old) treated with RISPERDAL® CONSTA® for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients [see DOSAGE AND ADMINISTRATION].
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether or not corrected for body weight) or race.
The effectiveness of RISPERDAL® CONSTA® in the treatment of schizophrenia was established, in part, on the basis of extrapolation from the established effectiveness of the oral formulation of risperidone. In addition, the effectiveness of RISPERDAL® CONSTA® in the treatment of schizophrenia was established in a 12-week, placebo-controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia.
Efficacy data were obtained from 400 patients with schizophrenia who were randomized to receive injections of 25 mg, 50 mg, or 75 mg RISPERDAL® CONSTA® or placebo every 2 weeks. During a 1-week run-in period, patients were discontinued from other antipsychotics and were titrated to a dose of 4 mg oral RISPERDAL®. Patients who received RISPERDAL® CONSTA® were given doses of oral RISPERDAL® (2 mg for patients in the 25-mg group, 4 mg for patients in the 50-mg group, and 6 mg for patients in the 75-mg group) for the 3 weeks after the first injection to provide therapeutic plasma concentrations until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.
Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated, multi-item inventory, composed of five subscales to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.
The primary efficacy variable in this trial was change from baseline to endpoint in the total PANSS score. The mean total PANSS score at baseline for schizophrenic patients in this study was 81.5.
Total PANSS scores showed significant improvement in the change from baseline to endpoint in schizophrenic patients treated with each dose of RISPERDAL® CONSTA® (25 mg, 50 mg, or 75 mg) compared with patients treated with placebo. While there were no statistically significant differences between the treatment effects for the three dose groups, the effect size for the 75 mg dose group was actually numerically less than that observed for the 50 mg dose group.
Subgroup analyses did not indicate any differences in treatment outcome as a function of age, race, or gender.
Bipolar 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 episodes.
Bipolar 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 the last 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.
Last reviewed on RxList: 12/28/2011
This monograph has been modified to include the generic and brand name in many instances.
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