Summary

• The maximum dose of RISPERDAL CONSTA is 50 mg every 2 weeks. No additional benefit was observed with dosages greater than 50 mg; however, a higher incidence of adverse events was observed in controlled trials in patients with schizophrenia. Dosages above 50 mg have not been studied in patients with Bipolar I Disorder.¹
• The use of higher then recommended doses has been reported in the medical literature.^2-20 The highest reported dose was 175 mg of RISPERDAL CONSTA, administered every 2 weeks.²⁰
• The highest dosage strength commercially available is 50 mg. No data is available in the published literature to specify how higher doses have been administered.

CLINICAL DATA

RISPERDAL CONSTA 62.5 mg every 2 weeks

Malempati et al (2011)²¹ evaluated the efficacy and tolerability of adjunctive RISPERDAL CONSTA in 10 adult patients (70% male; age range: 30-63 years old) diagnosed with Bipolar I or II Disorder and followed prospectively for 3 years. In this open-label study, 2 patients were maintained at a dose of 62.5 mg over the 3-year period.

Study Design/Methods

Patients with psychotic features who were refractory to earlier treatment were prescribed RISPERDAL CONSTA 25-62.5 mg every 2 weeks as an adjunct to mood stabilizers. Patients were evaluated at the initiation of treatment and then 6 weeks, 6 months, 1, 2, and 3 years after starting treatment.

Results

Efficacy

Two patients were maintained on a dose of 62.5 mg every 2 weeks. Initial CGI-S scores (7-point scale) were reduced from 7 to 2 during the 3-year treatment period and YMRS scores were reduced from 16 to 4 in both patients. Psychosis rating scale scores were reduced from 5 to 2 in 1 patient and 5 to 0 in the other patient. Both patients experienced 2 manic relapses (non-psychotic in 1 patient and very mild psychosis in the other patient) and 1 hospitalization during the 3-year RISPERDAL CONSTA treatment period.

Safety

One patient experienced a weight gain of 2 kg and both had mild extrapyramidal symptoms (EPS).

RISPERDAL CONSTA 75 mg every 2 weeks

Clinical trials designed to measure the efficacy and safety of RISPERDAL CONSTA 25, 50, and 75 mg every 2 weeks in patients with schizophrenia have been published. However, the 75 mg dose is not currently approved or recommended since no additional benefit was observed with dosages greater than 50 mg and a higher incidence of adverse events was seen with the 75 mg dose.

Double-Blind Trial

Kane et al (2003)² published the results from a 12-week, double-blind, placebo-controlled multicenter, randomized trial to evaluate the efficacy and tolerability of RISPERDAL CONSTA.

Study Design/Methods

Inpatients and outpatients (18-55 years) with schizophrenia and a baseline PANSS (Positive and Negative Syndrome Scale) score between 60-120 were included in the trial. Prior to the 12-week double-blind period, patients were screened for 1 week followed by a run-in phase of 1 week when previous treatments were discontinued and oral risperidone was initiated at 2 mg/day and then titrated up to 4 mg/day for at least 3 days. Patients then entered the double-blind period and were randomized to receive 6 injections of placebo, RISPERDAL CONSTA 25 mg, 50 mg or 75 mg every 2 weeks.

Oral risperidone supplementation was given to patients randomized to RISPERDAL CONSTA during the first 3 weeks of the double-blind phase. Patients randomized to receive RISPERDAL CONSTA 25 mg, RISPERDAL CONSTA 50 mg, and RISPERDAL CONSTA 75 mg were given oral risperidone 2 mg, 4 mg, and 6 mg, respectively. Patients randomized to receive placebo injections were given oral placebo supplementation. No oral supplementation was permitted during weeks 4-12 of the double-blind phase.

The PANSS was the primary measure of efficacy along with the CGI (Clinical Global Impression) scale. Safety and tolerability assessments included adverse events, vital signs, electrocardiograms, injection site pain assessments, and EPS by the ESRS (Extrapyramidal Symptom Rating Scale).

Results

The most common reasons for discontinuation were insufficient response, adverse event, and consent withdrawn. The discontinuation rate was 68% in the placebo group and 51-52% in the RISPERDAL CONSTA groups. For a summary of the Efficacy Results, see the Table: Efficacy Measures at Endpoint.

Safety

The most common adverse events are listed in the Table: Spontaneously-reported Adverse Events. Serious adverse events were reported in 23.5%, 13%, 14%, and 15% of patients in the placebo, RISPERDAL CONSTA 25-mg, 50-mg, and 75-mg groups, respectively.

Open-Label Trials

Fernandez-Miranda et al (2015)²² conducted a 3-yr prospective, observational study in 60 patients with severe (baseline CGI-S ≥5) schizophrenia.

Study Designs/Methods

Dosing of RISPERDAL CONSTA was ≥75 mg every 2 weeks. Endpoints included: CGI-S, hospitalizations, CAN, WHO Disability Assessment Schedule, and Medication Adherence Rating Scale.

Results

Efficacy

The completion rate at 3 years was 95%. The mean dose of RISPERDAL CONSTA was 111.2±9.1 mg every 2 weeks. Mean CGI-S decreased from 5.5 at baseline to 4.11 at year 3 (P<0.01). Hospital admissions decreased from a mean of 1.9 to 0.31 over the 3-year study (P<0.001). Disability decreased in 4 areas: self-care, occupational, family, and social impairment (all P≤0.05). CAN showed significant improvement (P<0.01) and adherence to medication improved (P<0.001).

Safety

Weight increased from 74.69 kg at baseline to 78.1 kg at year 3 and 32% gained >7% of body weight. Two patients discontinued, 1 due to sedation and 1 due to metabolic syndrome.

Gefvert et al (2005)³ conducted an open-label non-randomized study to evaluate the pharmacokinetics and central D₂ receptor occupancy of RISPERDAL CONSTA in stable patients aged 23-54 years with schizophrenia. This study also secondarily measured PANSS scores to evaluate treatment response and adverse events were recorded.

Study Designs/Methods

Thirteen outpatients with schizophrenia (12 male, 1 female) were included and their previous medications were discontinued. None of the patients had been treated with depot antipsychotics during the last year and no oral risperidone or clozapine were allowed the last 2 weeks before entering the study. Five consecutive injections of RISPERDAL CONSTA [25 (n=5), 50 (n=4), or 75 mg (n=4)] were given every 2 weeks as an intramuscular (IM) gluteal injection. The treating physician determined the dose for each patient, and they remained on their assigned dose for the duration of the study. Concomitant medications were allowed if they did not interfere with the metabolism of risperidone through direct or liver enzyme pathways.

Results

Efficacy

Eleven patients completed the trial. The mean total PANSS scores were low at inclusion (mean approximately 60) and improved in each treatment group. The mean PANSS scores improved 4% (-2.2), 21% (-13.0), and 11% (-6.5) in the 25, 50, and 75 mg RISPERDAL CONSTA groups, respectively.

Safety

Adverse events were reported by 2, 2, and 4 patients in the RISPERDAL CONSTA 25 mg, 50 mg, and 75 mg groups, respectively. Two patients experienced serious adverse events. One patient in the 25 mg group was hospitalized on day 8 for anxiety and 1 patient in the 75 mg group was hospitalized on day 76 for overdosing on flupentixol, alprazolam, and alcohol. EPS were observed in 1 patient receiving 75 mg who experienced mild akathisia.

Eerdekens et al (2004)⁴ describes the results from an open-label, 15-week, multicenter trial designed to compare the steady-state bioavailability of risperidone tablets given orally once per day and RISPERDAL CONSTA given every 2 weeks.

Study Design/Methods

Patients between the ages of 18-65 years with a DSM-IV diagnosis of schizophrenia were included. Patients stabilized on oral risperidone (2, 4, or 6 mg/day) for at least 1 month before the trial started were assigned to receive 25 mg, 50 mg, or 75 mg of RISPERDAL CONSTA IM every 2 weeks, respectively. During the first 3 weeks of the trial, the patients’ dose of oral risperidone remained the same as prior to trial initiation. The first IM injection of RISPERDAL CONSTA was given at the start of week 2. One-half of the oral risperidone dose was given during weeks 4-5 and no oral risperidone was given during weeks 6-15. Additional efficacy and safety assessments included PANSS, CGI, and ESRS scale scores, adverse events, vital signs, and injection site evaluation.

Results

Efficacy

A total of 86 patients were included in the trial. Clinical symptoms, as measured by the PANSS and CGI, remained stable or improved throughout the study in all 3 groups. The change from baseline to endpoint in the mean total PANSS score was -4.6 (P<0.01), -2.9, and -6.0 (P<0.05) in the 25 mg, 50 mg, and 75 mg RISPERDAL CONSTA groups, respectively. At the last RISPERDAL CONSTA on day 64 (at steady-state plasma levels), clinical improvement (20% or greater reduction in PANSS total scores) was noted in 44-57% of patients in the 3 groups. The change from baseline to endpoint on the Clinical Global Impressions - Severity of Illness (CGI-S) scale was -0.5, 0.0, and -0.3 in the 25 mg, 50 mg, and 75 mg groups, respectively.

Safety

Adverse events were reported by 76%, 81%, and 76% of patients in the RISPERDAL CONSTA 25 mg, 50 mg, and 75 mg groups, respectively. Adverse events occurring in 3 or more patients were: influenza-like symptoms, insomnia, condition aggravated, anxiety, depression, headache, tachycardia, nervousness, injury, fatigue, and agitation.

Fleischhacker et al (2003)⁵ published the results of a 1-year, open-label, international, multicenter, prospective trial in stable adult patients with schizophrenia.

Study Design/Methods

All patients had been receiving a stable dose of an antipsychotic for at least 4 weeks at initial screening and were judged by the investigator to be symptomatically stable. Other antipsychotics were discontinued and oral risperidone was given at a dose of 1 to 6 mg/day during the 2-week run-in period. RISPERDAL CONSTA (25, 50, or 75 mg) was given at day 1 and every 2 weeks thereafter for up to 50 weeks. The RISPERDAL CONSTA doses were determined by the oral risperidone dose at the end of the run-in period. Patients receiving up to 2 mg of oral risperidone started on RISPERDAL CONSTA 25 mg, patients receiving >2 mg up to 4 mg of oral risperidone started on RISPERDAL CONSTA 50 mg, and patients receiving >4 mg of oral risperidone started on RISPERDAL CONSTA 75 mg. Doses of RISPERDAL CONSTA could be adjusted as needed during the trial. Oral risperidone treatment (1-6 mg) was continued as supplementation for 2 or 3 weeks after the first RISPERDAL CONSTA.

Tolerability and Efficacy assessments included spontaneously reported adverse events, injection-site pain and reactions, ESRS, electrocardiograms, the PANSS, and the CGI-S. The primary Safety population included all patients who received at least 1 injection of RISPERDAL CONSTA. The primary Efficacy population included all patients who received at least 1 injection of RISPERDAL CONSTA and had at least 1 postbaseline assessment of efficacy.

Results

Baseline Characteristics

Six-hundred and sixty-three (663) patients were screened and 615 patients received at least 1 injection [25 mg (n=120), 50 mg (n=228), 75 mg (n=267)]. The average age of all patients was approximately 42 years and most patients were male (69%). Previous therapy included oral antipsychotics (n=481), mainly oral risperidone (n=369), and depot antipsychotics (n=233). Sixty-five percent of patients completed the trial. All 25 injections were received by 58% of patients. Twenty-three percent of patients in the RISPERDAL CONSTA 25 mg-group, 31% in the 50 mg-group, and 44% in the 75-mg group discontinued the trial. The most common reasons for discontinuation were withdrew consent, insufficient response, and adverse event.

Efficacy

Significant reductions at endpoint were noted on the PANSS total scores with all dose groups of RISPERDAL CONSTA. Clinical improvement was defined a priori as a 20% or greater reduction in PANSS total scores (Table: Efficacy Measures at Endpoint). At treatment endpoint, greater improvements were seen in the 25-mg and 50-mg groups than in the 75-mg group.

Efficacy Measures at Endpoint

Significant improvements from baseline were seen on the positive (P<0.01) and negative (P<0.001) PANSS subscales. According to the CGI-S, the proportions of patients who were rated as not ill, very mildly ill, or mildly ill increased from 58% at baseline to 78% at endpoint in the 25-mg group, from 40% to 65% in the 50-mg group, and from 33% to 44% in the 75-mg group. Eighteen percent of patients were rehospitalized during the trial.

Safety

Adverse events were reported in 85% of all patients during the trial and by 82%, 84%, and 87% of patients in the RISPERDAL CONSTA 25 mg, 50 mg, and 75 mg groups, respectively. The most common adverse events are listed in Table: Treatment Emergent Adverse Events. Five percent of patients discontinued the trial due to adverse events. The proportion of patients reporting adverse events declined from 68% during months 1-3 of the trial to 43% during months 10-12.

EPS were reported as adverse events in 25% of all patients, including 21% in the 25-mg group, 27% in the 50-mg group, and 25% in the 75-mg group. ESRS total scores improved from baseline in all treatment groups. The ESRS total score improved by 2.5 points at endpoint in the combined RISPERDAL CONSTA groups. Tardive dyskinesia (TD) was reported in 4 patients (0.7%). Six patients died during the trial: 4 by suicide (all with a diagnosis of paranoid schizophrenia), 1 of cardiac failure, and 1 of cardiac failure and pulmonary edema. The 2 deaths resulting from cardiac failure were not judged to be related to RISPERDAL CONSTA, but related to the patients’ underlying cardiac conditions and medical history.

A few additional articles also document the use of RISPERDAL CONSTA 75 mg or higher every 2 weeks. However, the Results are presented as an aggregate for patients receiving all doses of RISPERDAL CONSTA. The publications are cited for your review.^6-12,22-26

Case Reports

Case reports of RISPERDAL CONSTA 75mg every 2 weeks have been referenced.^13-15,27,28

RISPERDAL CONSTA 75 mg once monthly

Open-Label Trial

Gharabawi et al (2007)¹⁸ 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 ITT (intention-to-treat) population. Relapse was defined as 1 of the following: psychiatric hospitalization, increase in psychiatric care and a 25% increase in PANSS total score, within 2 weeks, Clinical Global Impressions of Change (CGI-C) score of 6 (much worse) or 7 (very much worse), or self-injury or violent behavior. 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.

Results

Efficacy

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. A total of 12 patients (17.9%) in the ITT population relapsed over 52 weeks, 6 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.

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 1 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. ESRS subscale scores for overall movement disorder subjective score, the physician's examination of parkinsonism, and the physician's examination of dyskinesia were unchanged or improved at endpoint. Mean scores on the ESRS dystonia and akathisia subscales were low (<1) at baseline and endpoint, while improvement on the parkinsonism subscale was significant at week 52 (P<0.05) and endpoint (P<0.01). There was an improvement measured on the total AIMS (Abnormal Involuntary Movement Scale) score, though the change from baseline was not significant at week 52 or endpoint. There were no clinically relevant changes in vital signs, electrocardiogram, or laboratory value parameters.

RISPERDAL CONSTA up to 100 mg every 2 weeks

Randomized trial

Meltzer et al (2014)²⁹ conducted a randomized, double-blind, 24-week, multicenter study comparing the Safety and Efficacy of high-dose RISPERDAL CONSTA (100 mg every 2 weeks) to a standard dose RISPERDAL CONSTA (50 mg every 2 weeks) for treatment resistant schizophrenia (TRS) (n=160).

Study Design/Methods

The primary endpoint of the study was the change from baseline to week 24 for the PANSS total score. Patients were assessed at baseline, then every 6 weeks until the end of the study. Key secondary endpoints were the change from baseline in the Personal and Social Performance Scale (PSP), and cognition.

Results

Efficacy

Both doses of RISPERDAL CONSTA appeared to be equally effective in improving psychopathology in TRS and 23.1% of patients no longer met the entry criteria for TRS. Significant improvements in mean PANSS total scores were observed regardless of dose. The mean PANSS total score at baseline was approximately 89 in both treatment groups, which decreased significantly to approximately 80 after 6-weeks treatment (P<0.001 for the comparison of each treatment group with baseline values). At week 24, both groups had PANSS total scores of approximately 71 and at no time was there a significant difference between the 2 groups.

The mean PSP total score at baseline was 40 in both treatment groups and it improved significantly after 6-weeks of treatment (P<0.0001 for the comparison of each treatment group with baseline values). The mean PSP total score was significantly different between the low- and high-dose RISPERDAL CONSTA groups only at week 12 and favored the 50 mg dose. At week 24, the mean PSP total score was approximately 51 in both groups. For cognition, a significant time effect was found for working memory (P<0.01) and declarative memory (P<0.05).

Safety

Plasma risperidone and 9-hydroxyrisperidone levels for the 100 mg group were approximately twice those of the 50 mg group at weeks 6 and 24. In addition, the mean prolactin concentrations increased significantly by approximately 50% in both groups by 6 weeks, with no further increases over the study. The most commonly reported adverse event reported in both treatment groups was parkinsonism (19% vs 17%, high-dose vs standard, respectively). The mean BMI increased by about 1 mg/m² in both treatment groups (P<0.0001 compared with baseline values). The percentage of patients gaining ≥7% in weight at week 24 was 24.6% in the RISPERDAL CONSTA 50 mg group and 20.4% in the RISPERDAL CONSTA 100 mg group.

Two articles document the use of RISPERDAL CONSTA at doses up to 100 mg. However, the results are presented as an aggregate for patients receiving all doses of RISPERDAL CONSTA. The publications are cited for your review.^7,23

Case Report

RISPERDAL CONSTA 125 mg every 2 weeks

Case Report

RISPERDAL CONSTA 100 mg - 175 mg every 2 weeks

Case Series

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 07 January 2025.