Summary

• RISPERDAL CONSTA should be administered every 2 weeks by deep intramuscular deltoid or gluteal injection.¹
• Administration of RISPERDAL CONSTA within 3 days before and 3 days after the approved dosing schedule of every 14 days (between days 11 and day 17 after the previous dose) was permitted during clinical studies.^2-5 There are no data from clinical trials to support the routine administration of RISPERDAL CONSTA maintenance doses at intervals shorter than every 14 days.
• The estimated 1-year risk of relapse was 22.4% in a 1-year, open label, pilot study of RISPERDAL CONSTA 50 mg administered once monthly in patients with schizophrenia or schizoaffective disorder.⁶
• Mathematical modeling was used to estimate blood levels in a variety of clinical scenarios during treatment with RISPERDAL CONSTA, including RISPERDAL CONSTA 50 mg administered every 4 weeks.⁷

PRODUCT LABELING

Please refer to the following section of the enclosed Full Prescribing Information which is relevant to your inquiry: DOSAGE AND ADMINISTRATION.

ALTERNATE DOSING REGIMENS

Once-monthly Dosing

Gharabawi et al (2007)⁶ conducted a 1-year, prospective, open-label, single-arm, multicenter, pilot study to explore the efficacy, safety, tolerability, and pharmacokinetics of RISPERDAL CONSTA 50 mg given once monthly in adult patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder.

Study Design/Methods

• The primary endpoint was time to relapse in the intention-to-treat (ITT) population.
• Relapse was defined by any one of the following: psychiatric hospitalization due to worsening symptoms, a significant increase in psychiatric care and a 25% increase from baseline in Positive and Negative Syndrome Scale (PANSS) total score within 2 weeks, substantial clinical deterioration, as indicated by a Clinical Global Impressions of Change (CGI-C) score of 6 (much worse) or 7 (very much worse), or deliberate self-injury, suicidal or homicidal ideation, or violent behavior resulting in property damage or clinically significant injury to another person.
• If criteria for relapse were met, the patient could discontinue from the study or continue on 75 mg once monthly, with oral risperidone supplementation during the first 3 weeks of the 75 mg dose period.
• During a 4-week lead-in period, patients received RISPERDAL CONSTA 50 mg every 2 weeks by intramuscular gluteal injection. Then RISPERDAL CONSTA 50 mg was given once monthly for 48 weeks. Patients were instructed to return for their long-acting injection within ± 3 days of their regularly scheduled visit. Oral risperidone supplementation (2-6 mg/day) was permitted for 2 weeks after the first injection only.

Results

Efficacy

• At baseline, the mean age was 39.8 years, 66.7% of patients were male, and 78.2% had a diagnosis of schizophrenia, and mean PANSS total score was 65.4.
• Sixty-seven (n=67) patients received ≥1 dose of medication and had ≥1 Efficacy evaluation after week 4 and were included in the Efficacy ITT population.
• The estimated 1-year risk of relapse was 22.4% (95% CI 10.9-33.9%) in the ITT population.
• A total of 12 patients (17.9%) in the ITT population relapsed over 52 weeks, six patients required psychiatric hospitalization and 6 patients had substantial clinical deterioration. Eight of these patients consequently received treatment with 75 mg once monthly and none of them relapsed. Of these 8 patients, efficacy information was available for 6 patients. The mean PANSS total score at baseline (the beginning of the 75 mg dose period) was 88.4 and improved to 65.8 at endpoint. The mean CGI-S score at baseline was 5.0 and improved to 4.2 at endpoint.
• The mean PANSS total score improved significantly at all time points during the trial, including week 52 (P<0.0001), but not at endpoint.
• Improvements from baseline were also noted on the PANSS factor scores (positive, negative, anxiety/depression, uncontrolled hostility/excitement, and disorganized thought) at week 52 (P<0.01), but not at endpoint.
• The mean Clinical Global Impressions-Severity (CGI-S) score improved significantly from baseline at week 52 (P=0.0002), but not at endpoint.
• The percentage of patients with a CGI-S rating of “not ill” to “mildly ill” increased from 50.8% at baseline to 62.7% at endpoint.
• RISPERDAL CONSTA 50 mg once monthly resulted in average plasma concentration of the active moiety (risperidone and 9-hydroxyrisperidone) of 17.5 ng/mL and a fluctuation index of 199% in samples obtained from 18 patients during steady state.

Safety

• A total of 87 patients received ≥1 dose of RISPERDAL CONSTA and were included in the safety analysis.
• Adverse events were not reported separately for the RISPERDAL CONSTA 75 mg once monthly patients. However, in total, 67 of 87 patients (77.0%) experienced at least one adverse event.
• The most frequently reported adverse events in >10% of patients were schizophrenia aggravated not otherwise specified (19.5%), anxiety (16.1%), insomnia (16.1%), and headache (11.5%).
• Nine patients discontinued the trial due to adverse events.
• Tremor (4.6%) was the most frequently reported movement disorder-related adverse event.

Authors’ Conclusions

• The authors stated that once-monthly dosing of RISPERDAL CONSTA appeared to maintain the baseline symptomatic status of stable patients with schizophrenia or schizoaffective disorder, with no unexpected safety and tolerability results.
• Interpretations are limited, however, due to the open-label design, small sample size, and lack of concurrent biweekly treatment arm. Future controlled trials are warranted.

Uchida et al (2008)⁸ conducted a positron emission tomography (PET) study to evaluate the striatal dopamine D₂ receptor binding with intramuscular administration of RISPERDAL CONSTA 50 mg once monthly.

Study Design/Methods

• Participants were recruited from a 1-year, multicenter study involving adult patients diagnosed with schizophrenia or schizoaffective disorder conducted by Gharabawi et al (2007).⁶
• Participants who received at least 3 monthly injections of RISPERDAL CONSTA 50 mg in the primary were referred to undergo a PET scan within 4 days of the next monthly injection.

Results

• Seven participants (male, n=6; mean age, 35 years; mean duration of illness, 11.9 years) completed the PET study.
• The mean total plasma concentration of risperidone plus 9-hydroxyrisperidone was 16.6±12.3 ng/mL (range, 5.7-40.8 ng/mL).
• The mean D₂ receptor occupancy was 56%±24% (range, 29%-82%), and 3 participants achieved D₂ receptor occupancy >60%. The four participants who did not reach >60% occupancy did not relapse in the 1-year of follow-up.

Authors’ Conclusions

• The authors conclude that sustained D₂ receptor occupancy >60% may not be necessary to maintain clinical Efficacy, suggesting clinical implications on dosing regimens. However, further investigation is warranted.

Wilson et al (2004)⁷ 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. 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.

The following 3 dosing strategies and the expected range of resulting blood levels (ng/ml) were modeled: 1) 25 mg every 2 weeks (13-22 ng/ml) 2) 37.5 mg every 3 weeks (11-25 ng/ml) and 3) 50 mg every 4 weeks;(6-34 ng/ml). The dosing scenario of 50 mg every 4 weeks produced high peaks and deep troughs, indicating a lack of continuous treatment.

SELECTED ADDITIONAL REFERENCES

An analysis of RISPERDAL CONSTA use in elderly patients has been cited for your reference, as one patient in the analysis was managed on RISPERDAL CONSTA 37.5 mg every 4 weeks because he found injections unpleasant.⁹

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 27 April 2023.