Summary

• RISPERDAL CONSTA is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder. The recommended dose of RISPERDAL CONSTA for the maintenance treatment of Bipolar I Disorder is 25 mg intramuscular (IM) every 2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Doses above 50 mg have not been studied in this population.¹
• In a randomized, double-blind, placebo-controlled study in patients with Bipolar I Disorder, treatment with RISPERDAL CONSTA significantly delayed the time to relapse of mood episodes compared to placebo. In the RISPERDAL CONSTA group, 30% of patients relapsed versus 56% in the placebo group. Adverse events occurring more commonly in the RISPERDAL CONSTA group compared to placebo (≥3% difference) were depression and weight increase.²
• In a 52-week, double-blind, randomized, placebo-controlled study in patients with a history of Bipolar I Disorder who relapse frequently, treatment with adjunctive RISPERDAL CONSTA plus treatment as usual (TAU) significantly delayed the time to relapse of a mood episode compared to placebo plus TAU. In the RISPERDAL CONSTA plus TAU group, 23.1% of patients relapsed versus 45.8% in the placebo plus TAU group. The most common adverse events (≥10%) were tremor, insomnia, muscle rigidity, and mania.³
• A randomized, double-blind, placebo-controlled study of acute or nonacute patients with Bipolar I Disorder assessed the time to recurrence of any mood episode with RISPERDAL CONSTA, olanzapine, or placebo. In a stratified analysis, there was no difference between RISPERDAL CONSTA and placebo on this primary outcome measure, but time to recurrence of any mood episode was significantly longer with RISPERDAL CONSTA versus placebo in an adjusted analysis.⁴

Double-Blind Trials

International Study Evaluating the Safety and Efficacy of RISPERDAL CONSTA in Preventing the Recurrence of Mood Episodes in Bipolar I Disorder

Vieta et al (2012)⁴ presented the results of an international, randomized, double-blind, double-dummy study to evaluate the efficacy and safety of RISPERDAL CONSTA compared with placebo in preventing the recurrence of mood episodes in Bipolar I Disorder.

• Recurrence events were defined as: Met diagnostic and statistical manual (DSM-IV-TR) criteria for a hypomanic, manic, mixed, or depressive episode; Required treatment intervention with any mood stabilizer, antipsychotic medication (besides study drug), antidepressant, or benzodiazepine (greater than the allowed dosage); Required hospitalization for any bipolar mood episode; Clinical Global Impressions-Severity (GCI-S) score ≥4 and either Young Mania Rating Scale (YMRS) score >12 or Montgomery Asberg Depression Rating Scale (MADRS) score >12; Required an increased dose of study medication during period 3, or required supplementation with oral risperidone or another antipsychotic or mood stabilizer.

Study Design/Methods

• Included patients (aged 18-65 years) were classified as acute or nonacute based on YMRS and clinical global impression—severity (CGI-S) scores and were required to have had at least 2 prior mood episodes in the previous year. Nonacute patients must have been stable on an antipsychotic or mood stabilizer for at least 4 weeks prior to screening and must have experienced Safety or tolerability problems or requested a medication change. Patients were followed for up to 18 months or until 158 recurrence events occurred.
• The trial consisted of 3 periods: Period 1 was a 2-week screening period in which nonacute patients continued their current medication while acute patients received treatment according to the investigator’s discretion; Period 2 consisted of treatment with RISPERDAL CONSTA every 2 weeks at a dose of 25, 37.5, or 50 mg. Patients had a fixed dose starting at week 8; Period 3 included patients who did not experience a defined recurrence event during period 2. These patients were randomized to a fixed dose of RISPERDAL CONSTA at the dose they were receiving at the end of period 2 plus oral placebo; oral plus injectable placebo; or oral olanzapine 10 mg and injectable placebo (included for reference and exploratory comparisons to placebo only).

Results

The mean patient age (ITT population) was 36.9 years, 52% were female, and 72% entering period 3 were considered acute at the time of screening. Period 2 included 553 patients, and 398 patients entered period 3. In patients randomized to RISPERDAL CONSTA, the fixed dose was 25 mg (66%), 37.5 mg (31%), or 50 mg (4%).

Efficacy

• On the primary endpoint, time to recurrence of any mood episode during period 3, there was no difference between the RISPERDAL CONSTA and placebo groups (P=0.057) when the analysis was stratified by patient type and region. However, a post hoc analysis, stratified only by region, showed that the RISPERDAL CONSTA group had a significantly longer time to first recurrence of any mood episode (P=0.031). In addition, time to recurrence of a hypomanic, manic, or mixed mood episode was significantly longer in the RISPERDAL CONSTA group in both the prespecified (P=0.005) and in the adjusted analyses (P=0.002), but there was no difference between groups in time to recurrence of a depressive episode.
• There were statistically significant differences in favor of RISPERDAL CONSTA versus placebo during period 3 in YMRS total score (P<0.001) and CGI-S total score (P<0.001), but not MADRS total score (P=0.480). There was a statistically significant difference on the primary endpoint between olanzapine and placebo in both analyses (P≤0.010). For patients receiving olanzapine and compared with placebo, YMRS (P≤0.001) and MADRS (P≤0.001) scores remained stable, and CGI-S scores increased to a lesser extent than placebo (P≤0.001). This study did not include any planned comparisons between RISPERDAL CONSTA and olanzapine.

Safety

• In period 3, 21% and 16% of RISPERDAL CONSTA and placebo patients, respectively, discontinued treatment.
• The most common adverse events during period 3 were weight increase (24%), insomnia (17%), and amenorrhea (8%) in the RISPERDAL CONSTA group, and insomnia (18%), mania (16%), and weight increased (9%) with placebo. In olanzapine patients, the most common adverse events were weight increased (25%), somnolence (14%), insomnia (10%), and headache (9%).
• Weight increase ≥7% occurred in 18% of RISPERDAL CONSTA patients versus 5% of placebo and 28% of olanzapine patients. Hyperprolactinemia occurred in 2 patients in the RISPERDAL CONSTA group, and diabetes mellitus was reported in 2 patients receiving RISPERDAL CONSTA.

Study Evaluating RISPERDAL CONSTA for the Prevention of Mood Episodes in Patients with Bipolar I Disorder

Quiroz et al (2010)² presented results from an international, randomized, double-blind, placebo-controlled, multicenter study evaluating the use of RISPERDAL CONSTA for the prevention of mood episodes in adult patients (18-65 years of age) with Bipolar I Disorder. Patients (n=559) included were currently experiencing an acute manic or mixed episode (YMRS ≥20) or were stable (CGI-S ≤3) on oral risperidone, RISPERDAL CONSTA, other oral antipsychotics, or mood stabilizers but, due to Safety or tolerability concerns, required a medication change.

Study Design/Methods

• The study consisted of 5 periods (Period 1 was Screening, Period 5 was Open-Label Extension):
  • Period 2 (3 weeks): Open-Label Oral Risperidone Treatment (patients stable on other antipsychotics/mood stabilizers were titrated off and started on oral risperidone by day 8).
  • Period 3 (26 weeks): Open-Label RISPERDAL CONSTA Stabilization (patients stable on risperidone before the study and those that achieved an initial response [CGI-S ≤3] during the open-label oral risperidone phase were enrolled in a RISPERDAL CONSTA stabilization phase at doses of 12.5-50 mg every 2 weeks).
  • Period 4 (up to 24 months): Double-Blind, Placebo-Controlled Withdrawal Phase (stabilized patients maintaining a treatment response during the stabilization phase entered a double-blind treatment phase and were randomized to either long-acting injection [at the dose received during the last 8 weeks of the stabilization phase; no titration allowed] or placebo; patients continued in the double-blind phase until they either completed 24 months, met relapse criteria, withdrew from the study, or ceased treatment for other reasons).
• Concomitant use of oral risperidone (first 3 weeks of period 3 following RISPERDAL CONSTA initiation [1-6 mg/day] and first 3 weeks following any increase in RISPERDAL CONSTA dosage [1-2 mg/day]), nonbenzodiazepine hypnotics, benzodiazepines (not within 8 hours of efficacy assessment), propranolol, and anticholinergic medications were permitted.
• The primary measure was time to relapse of a mood episode during the double-blind phase.
  • Relapse was defined as meeting any 1 of the following criteria: Met DSM-IV criteria for a manic, hypomanic, mixed, or depressive episode; Required treatment intervention with any mood stabilizer, antipsychotic medication (besides study drug), antidepressant, or benzodiazepine (greater than the allowed dosage); Required hospitalization for any bipolar mood episode; YMRS score >12, CGI-S score >4, or MADRS score >12; Required an increase in RISPERDAL CONSTA dose or supplementation with oral risperidone.

Results (Phase 1-4)

Of the 559 patients who entered the study, 303 entered the double-blind phase (154 RISPERDAL CONSTA, 149 placebo). Seventy-seven percent of RISPERDAL CONSTA patients received a dose of 25 mg every 2 weeks. The median duration of exposure for patients on RISPERDAL CONSTA and placebo was 280.5 days and 151 days, respectively. The mean age at screening was 39 years, with 49% and 54% males in the RISPERDAL CONSTA and placebo groups, respectively. At screening, 40% of patients from both groups were experiencing an acute episode, with 76% of patients in the RISPERDAL CONSTA group and 83% of patients in the placebo group experiencing a manic-type episode.

Efficacy

• There was a significant delay in time to relapse of a mood episode for patients treated with RISPERDAL CONSTA compared to placebo (P<0.001).
• During the double-blind phase, a total of 30% of patients in the RISPERDAL CONSTA group relapsed, compared to 56% of patients in the placebo group. Based on Kaplan-Meier estimates, 30% of patients treated with RISPERDAL CONSTA relapsed by 9 months compared to 60% of patients treated with placebo (NNT=3.3).
• In the RISPERDAL CONSTA group, the type of relapse episode was evenly divided (elevated mood: 16%; depressed mood: 14%). However, in the placebo group, a greater number of patients had elevated mood (46%) than depressive mood (10%). Compared to patients in the placebo group, RISPERDAL CONSTA patients experienced a significantly longer time to recurrence of elevated mood episodes (P<0.001; HR [95% CI]: 0.25 [0.15-0.41]) but not depressive episodes.
• RISPERDAL CONSTA was significantly better at maintaining YMRS, MADRS, and CGI-S scores compared to placebo.

Safety

• During the double-blind phase, treatment-emergent adverse events occurred in 53% of patients from both treatment groups. A total of 27 patients experienced a serious treatment-emergent adverse event leading to discontinuation from the study, with all cases being due to relapses.
• Weight increase ≥7% occurred in 15% of patients from the baseline to the end of the open-label stabilization phase. In the double-blind period, weight increase ≥7% occurred in 12% of patients receiving RISPERDAL CONSTA and 3% of patients in the placebo group. In the double-blind phase, 10% of patients in the RISPERDAL CONSTA group (1 patient discontinued due to hyperglycemia) and 3% of patients in the placebo group (1 patient discontinued due to weight increase) experienced glucose-related adverse events.
• Treatment-emergent extrapyramidal symptom (EPS)-related adverse events occurred in 3% of RISPERDAL CONSTA patients and 2% of placebo patients during period 4. There were 2 reports of tardive dyskinesia during the open-label risperidone phase, 1 of which led to discontinuation.
• Three patients died in the study, 1 during the open-label oral risperidone phase (perforated duodenal ulcer and peritonitis), and 2 during the open-label stabilization phase (accidental fall; chemical poisoning/completed suicide).

Double-Blind, Prospective, Randomized, Placebo-controlled, International Study in Adult Patients with Bipolar I or II Disorder

Macfadden et al (2009)³ conducted a double-blind, prospective, randomized, placebo-controlled, international study in adult patients (18-70 years of age) with Bipolar I or II Disorder who relapse frequently (defined as at least 4 mood episodes in the past 12 months requiring psychiatric intervention). The 2-phase study included an open-label stabilization phase (16 weeks; Bipolar I Disorder: n=240; Bipolar II Disorder: n=35) and a double-blind relapse-prevention phase (up to 52 weeks; Bipolar I Disorder: n=124; Bipolar II Disorder: n=15). Due to the low enrollment in the Bipolar II Disorder population, the published results focus on the Bipolar I Disorder population. Results from the total study population (Bipolar I and II Disorder) were presented at the American Psychiatric Association Annual Meeting in 2006 (open-label stabilization: Kujawa et al [2006]⁵) and the Institute on Psychiatric Services Annual Meeting in 2008 (double-blind relapse-prevention phase: Alphs et al [2008]⁶).

Study Design/Methods

• During the open-label phase, patients received RISPERDAL CONSTA 25 to 50 mg every 2 weeks (flexible dosing) plus TAU. TAU included treatment with antidepressants, mood stabilizers, or anxiolytics as determined by the investigator. During the first 3 weeks after RISPERDAL CONSTA initiation, patients continued their preexisting oral antipsychotic regimens; for those not previously receiving oral antipsychotics, oral risperidone was given. During the double-blind phase, patients were randomized to receive either RISPERDAL CONSTA plus TAU or placebo plus TAU.
• Short-term intermittent use of rescue medication (e.g., lorazepam, risperidone) was permitted.
• To enter the double-blind phase, patients were required to meet stable remission criteria in weeks 12 through 16 of the open-label phase. Criteria for stable remission included no active mood disorder, no hospitalizations or crisis interventions, no change in psychotropic medication doses, YMRS and MADRS scores of ≤10, and Clinical Global Impressions for Bipolar Disorder - Severity (CGI-BP-S) score ≤3.
• Patients not achieving remission after the 16-week open-label phase could continue open-label RISPERDAL CONSTA and TAU through week 52 as nonremitted continuing (NRC) patients.⁷
• The primary outcome of the double-blind phase was time to relapse, as determined by an independent relapse monitoring board. Relapse was defined as a DSM-IV-TR acute mood episode during compliance with the oral TAU regimen AND at least 1 of the following:
  • Hospitalization for worsening of manic or depressive symptoms AND significant suicidal ideation determined by an InterSePT Scale for Suicidal Thinking (ISST) revised score >7
  • Hospitalization for worsening of manic or depressive symptoms AND
    • YMRS or MADRS score >15 AND
    • CGI-BP-S score ≥4, or CGI-BP-C score ≥6, or decrease in Global Assessment of Functioning (GAF) score by >10 points from baseline
  • Clinical worsening necessitating a new mood stabilizer, antidepressant, or antipsychotic, or requirement for a >20% increase in existing oral TAU dosage AND
    • YMRS or MADRS score >15 AND
    • CGI-BP-S score ≥4, or CGI-BP-C score ≥6, or decrease in GAF score by >10 points from baseline

Results

Open-Label Phase - Efficacy

• The Bipolar I Disorder patients enrolled in the open-label phase (n=240) had a mean age of 38.4 years and 60% were male. A total of 183 patients (76.3%) completed the open-label phase.
• RISPERDAL CONSTA modal dose during the stabilization phase was 25 mg in 79.2%, 37.5 mg in 19.6%, and 50 mg in 1.3%.
• At the 16-week endpoint, there were significant improvements from baseline (P≤0.001) on YMRS, MADRS, and CGI-BP-S (overall, mania, and depression) scores.
• A total of 124 patients (51.7% of patients who entered the open-label stabilization phase) met inclusion criteria for the double-blind phase and were randomized to receive RISPERDAL CONSTA plus TAU (n=65) or placebo plus TAU (n=59).

Double-Blind Phase - Efficacy

• At double-blind baseline, the group assigned to RISPERDAL CONSTA plus TAU had a mean age of 40.0 years, 70.8% were male, and 81.5% were Indian. The placebo plus TAU group had a mean age of 37.6 years, 72.9% were male and 84.7% were Indian.
• During the double-blind phase, in the RISPERDAL CONSTA plus TAU group, modal doses of RISPERDAL CONSTA were 25 mg (67.7%), 37.5 mg (27.7%), and 50 mg (4.6%).
• A Kaplan-Meier survival analysis indicated that time to relapse was significantly longer in patients assigned to RISPERDAL CONSTA plus TAU than in those assigned to placebo plus TAU (P=0.010). Over the 52-week period, fewer patients in the group assigned to RISPERDAL CONSTA plus TAU (23.1%; n=15) relapsed than did in the group assigned to placebo plus TAU (45.8%; n=27).
• For patients who relapsed, fewer patients in the RISPERDAL CONSTA group than in the placebo group relapsed to a depressive episode (12.3% vs 18.6%), a manic episode (7.7% vs 20.3%), or a mixed episode (3.1% vs 6.8%). The relative risk of independent monitoring board-determined relapse was 2.3 and did not differ among types of relapse episodes, indicating that the risk of relapse was significantly higher with placebo plus TAU than with RISPERDAL CONSTA plus TAU (P=0.011). This finding was supported by a secondary analysis of the principal investigator-determined relapse number (P=0.024)³ and a subanalysis (Turner et al [2009]⁸), which found that the relative risk of principal investigator-determined relapse was similar to that of independent monitoring board-determined relapse (2.1-fold risk favoring adjunctive RISPERDAL CONSTA; P=0.022).
• Improvements in YMRS, MADRS, CGI-BP-S (overall, mania, and depression) scores seen during the open-label study were maintained throughout the double-blind phase in the group assigned to RISPERDAL CONSTA plus TAU. Total YMRS scores in patients assigned to placebo plus TAU worsened during the double-blind phase.

Safety

• Discontinuations due to adverse events occurred in 3 patients assigned to RISPERDAL CONSTA plus TAU and 1 patient assigned to placebo plus TAU.
• More patients assigned to placebo plus TAU (22.0%) experienced ≥1 serious adverse event than patients assigned to RISPERDAL CONSTA plus TAU (13.8%); however, most of these events were related to underlying illness.
• The most common adverse events (≥10% incidence) reported in either group (RISPERDAL CONSTA + TAU [n=65]; Placebo [PBO] + TAU [n=59]) during the double-blind study were tremor (RISPERDAL CONSTA+TAU 24.6%; PBO+TAU 10.2%), insomnia (RISPERDAL CONSTA+TAU 20%; PBO+TAU 18.6%), muscle rigidity (RISPERDAL CONSTA+TAU 12.3%; PBO+TAU 5.1%) and mania (RISPERDAL CONSTA+TAU 4.6%; PBO+TAU 13.6%).³
• A higher proportion of patients assigned to RISPERDAL CONSTA plus TAU (30.8%) than of those assigned to placebo plus TAU (16.9%) experienced at least 1 EPS-related adverse event; however, all events were assessed to be of low severity at double-blind baseline and endpoint in both treatment groups. Hypokinesia occurred in 7.7% of patients in the group receiving RISPERDAL CONSTA plus TAU and in 0 patients in the group receiving placebo plus TAU, while akathisia occurred in 4.6% and 6.8%, respectively.
• Weight gain occurred in 6.2% of patients in the group receiving RISPERDAL CONSTA plus TAU and in 1.7% of patients in the group receiving placebo plus TAU. During the open-label stabilization phase, patients gained a mean of 2.6 kg while receiving RISPERDAL CONSTA plus TAU. During the double-blind phase, patients assigned to RISPERDAL CONSTA plus TAU underwent a mean body weight increase of 0.7 kg from the end of the open-label stabilization phase to the double-blind endpoint; those assigned to placebo plus TAU lost a mean of 2.0 kg during the same interval (P=0.002).
• Mean prolactin levels were 24.4 ng/mL for the group receiving RISPERDAL CONSTA plus TAU and 36.4 ng/mL for the group receiving placebo plus TAU at the double-blind baseline. At double-blind endpoint, prolactin levels had increased (mean, 14.3 ng/mL) with RISPERDAL CONSTA plus TAU and decreased (mean, 20.9 ng/mL) with placebo plus TAU (P<0.001). Potential prolactin-related adverse events were reported in 6.2% of patients in the RISPERDAL CONSTA plus TAU group and in 5.1% of patients in the placebo plus TAU group.
• Three deaths were reported during the trial. One patient in the RISPERDAL CONSTA plus TAU group had hypertensive heart disease unrelated to study medication and 2 patients in the placebo plus TAU group died of motor vehicle accident and suicide.

Subanalyses

Several post hoc and subanalyses have been conducted using data from previously published studies that evaluated RISPERDAL CONSTA for the treatment of Bipolar Disorder. These analyses assessed differences in treatment response⁹, reported results from the subgroup of patients with Bipolar Disorder who were enrolled in the Switch to Risperidone Microspheres (StoRMi) study¹⁰, presented Results from 70 nonremitted patients from the MacFadden et al (2009) trial³ who continued treatment with RISPERDAL CONSTA⁷, and compared efficacy and safety of RISPERDAL CONSTA in patients from the United States and India.¹¹ Three additional post hoc analyses of the MacFadden et al (2009) trial³ evaluated suicidal thinking¹², mood symptoms¹³, and predictors of remission¹⁴ in patients with Bipolar Disorder who frequently relapsed.

Open-Label Studies

OTHER RELEVANT LITERATURE

A real-world effectiveness study²¹ has been included in the References section below.

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 26 November 2024. Retrospective studies and case reports/case series have not been included in this reply.