Summary

• Steady state plasma concentrations of RISPERDAL CONSTA are reached after 4 injections (administered every 2 weeks) and are maintained for 4-6 weeks after the last injection.¹
• After a single intramuscular injection of RISPERDAL CONSTA, there is a small initial release of the drug, followed by a lag time of 3 weeks. Upon erosion of the microspheres and subsequent absorption of risperidone, the apparent half-life of RISPERDAL CONSTA is 3-6 days. Therefore, the elimination phase of RISPERDAL CONSTA is complete approximately 7-8 weeks after the last injection.¹
• In an extension of a 24-month open-label study, 78.8% of patients with schizophrenia relapsed after discontinuation of RISPERDAL CONSTA. Some of these patients were tapered off medication.^{2, 3}

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

CLINICAL STUDIES

Published Literature

Samtani et al (2012)⁴ conducted a pharmacokinetic simulation model to evaluate antipsychotic plasma concentrations after discontinuation or interruption of therapy with oral and long-acting injectable formulations of risperidone and paliperidone. The results for RISPERDAL CONSTA are presented below. The simulation assumed individuals were at steady state and then entered into 1 of 3 separate discontinuation/interruption scenarios, with medication-specific reinitiation strategies used in the interruption scenarios:

• Scenario 1: complete discontinuation
• Scenario 2: one week treatment interruption followed by administration of RISPERDAL CONSTA 37.5 mg every 2 weeks
• Scenario 3: four weeks of treatment interruption, followed by RISPERDAL CONSTA 37.5 mg every 2 weeks and risperidone oral 3 mg once daily supplementation from day 28 to day 49 (ie, weeks 4-7)

Pharmacokinetic modeling was used to predict plasma concentrations over an 8 week period following treatment discontinuation or interruption, and to determine the lowest concentrations during the modeled period as a percentage of the steady-state minimum plasma concentration (C_min) in the 2 interruption scenarios.

• Scenario 1: complete treatment discontinuation - discontinuation of RISPERDAL CONSTA resulted in the active moiety concentration continuing to approximate the steady-state concentration for approximately 3-5 weeks due to delay in release (main release of drug is maintained from 4-6 weeks after injection). A rapid decline of active moiety concentration is observed with near zero concentration reached by week 5.
• Scenario 2: one week treatment interruption - in patients receiving RISPERDAL CONSTA, the active moiety concentration decreased to 35% of steady-state minimum concentrations after 4-5 weeks following treatment interruption.
• Scenario 3: four week treatment interruption - the active moiety plasma concentration in the RISPERDAL CONSTA group decreased to 33% of the steady-state minimum concentration. Upon reinitiation with RISPERDAL CONSTA and oral risperidone, the plasma concentration increased above the steady-state C_min in less than 1 week. Because of the delayed release characteristics in the RISPERDAL CONSTA group, concentrations decreased again between weeks 7 and 8, occurring just after discontinuation of oral supplementation.

The authors concluded that formulations with a longer half-life result in a resilient pharmacokinetic profile in the event of treatment discontinuation or interruption in subjects at steady state. After treatment was interrupted, active moiety plasma concentrations decreased more gradually and to a lesser extent with the long-acting injectable formulations of antipsychotics, such as RISPERDAL CONSTA, than with orally administered formulations. Upon clinically advised discontinuation, the prolonged-release characteristics of medications with a long half-life need to be considered.

Wilson et al (2004)⁵ used mathematical modeling to estimate blood levels in a variety of clinical scenarios during treatment with RISPERDAL CONSTA. A model of single-dose pharmacokinetics was derived from a study reporting blood levels (n=26) after a single dose of 50 mg RISPERDAL CONSTA. A mathematical model was used to prepare graphs of expected multiple-dose schedules consistent with clinical situations. Empirically validated assumptions were used. By using linear pharmacokinetics, the authors derived 25 and 37.5 mg RISPERDAL CONSTA models and graphs. While expected blood levels in a variety of clinical practice situations are described, the exact correlation between antipsychotic blood levels and clinical response during treatment is not completely understood.

Modeling of steady-state blood levels, from 25 mg RISPERDAL CONSTA given every 2 weeks, reflects significant blood levels of the active moiety (risperidone and 9-hydroxy-risperidone) being maintained for about 6 weeks following the last injection.

Unpublished Literature

Emsley et al (2009)^{2, 3} conducted an extension of a 24-month open-label study with risperidone long-acting injection to determine relapse rates after medication discontinuation. In this prospective extension, 33 patients with first-episode schizophreniform disorder or schizophrenia who successfully completed 2 years of treatment with RISPERDAL CONSTA opted to discontinue treatment. RISPERDAL CONSTA was tapered down over a period of up to 6 weeks. Doses greater than 25 mg were tapered down to 25 mg every 2 weeks in 1 or 2 steps and then discontinued. At the time of treatment discontinuation, 60.6% of patients were receiving 25 mg, 30.3% were receiving 37.5 mg, and 9.1% were receiving 50 mg every 2 weeks. Six patients were tapered off RISPERDAL CONSTA, and the median duration of use after baseline was 15 days (range, 0-44 days). After discontinuation, relapse occurred in a total of 26 patients (78.8%), with a median time to relapse of 163 days. In this study the baseline demographics, symptom severity, and remission status prior to medication discontinuation did not predict relapse. A rapid return of symptoms at relapse was not detected by early changes in Positive and Negative Syndrome Scale scores.

LITERATURE SEARCH

A literature search of MEDLINE^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 23 August 2023.