Summary

• RISPERDAL CONSTA (risperidone long-acting injection), an atypical antipsychotic, is approved for the treatment of schizophrenia as well as the maintenance treatment of Bipolar I Disorder as monotherapy or as adjunctive therapy to lithium or valproate.¹
• In a pivotal 12-week, double-blind, placebo-controlled trial in patients with schizophrenia, there were significant improvements in the RISPERDAL CONSTA groups on the PANSS (Positive and Negative Syndrome Scale) total, positive, and negative subscale scores as measured from baseline to endpoint (P<0.05 vs. placebo). The most common adverse events (≥10%) were headache, agitation, psychosis, insomnia, anxiety, dizziness, extrapyramidal disorder, hyperkinesia, somnolence, hypertonia, rhinitis, and pain.²
• Results from a 52-week, double-blind, randomized, placebo-controlled study in patients with a history of Bipolar I Disorder who relapse frequently demonstrated that treatment with adjunctive RISPERDAL CONSTA plus TAU (treatment as usual) significantly delayed the time to relapse of a mood episode compared to treatment with placebo plus TAU. In the RISPERDAL CONSTA plus TAU group, 23.1% of patients relapsed, compared with 45.8% in the placebo plus TAU group. The most common adverse events (≥10%) were tremor, insomnia, muscle rigidity, and mania.³
• Results from a randomized, double-blind, placebo-controlled study in patients with Bipolar I Disorder demonstrated that 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 compared to 56% in the placebo group. The adverse event occurring more commonly in the RISPERDAL CONSTA group compared to placebo (≥3% difference) was weight increase.⁴

PRODUCT LABELING

Please refer to the enclosed Full Prescribing Information for additional information relevant to your inquiry.

CLINICAL STUDIES – SCHIZOPHRENIA

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.

Although this trial of RISPERDAL CONSTA in schizophrenia included a 75 mg dose given every 2 weeks, the maximum recommended dose of RISPERDAL CONSTA is 50 mg every 2 weeks.

Double-Blind, 12-Week 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, in good general health, and a baseline PANSS (Positive and Negative Syndrome Scale) score between 60-120 were included in the trial.
• There was a one-week screening phase followed by a one-week run-in phase 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 three days.
• Patients then entered the double-blind period and were randomized to receive six injections of placebo, RISPERDAL CONSTA 25 mg, 50 mg, or 75 mg every two 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, 50 mg, and 75 mg were given supplemental oral risperidone 2 mg, 4 mg, and 6 mg, respectively during the first 3 weeks of the double-blind phase. 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 primary efficacy measure was change in PANSS total scores. Secondary Efficacy measures included the Clinical Global Impression (CGI) scale and percentage of patients achieving clinical improvement (≥ 20% reduction in PANSS total score).
• Safety and tolerability outcomes included adverse events, vital signs, electrocardiograms, injection site pain assessments, and extrapyramidal symptoms by the Extrapyramidal Symptom Rating Scale (ESRS).

Results

• Four hundred patients with schizophrenia entered the double-blind period, and 370 were included in the intent-to-treat analysis (at least 1 injection and 1 post-baseline assessment).
• According to a Kaplan-Meier analysis, the dropout rate was similar in the four treatment groups during days 1-15, after which more placebo patients than patients receiving RISPERDAL CONSTA discontinued treatment.
• The average age of the patients was approximately 38 years and median previous hospitalizations were approximately 4. Equal proportions were outpatients and hospital inpatients.
• There were significant improvements from baseline on the PANSS total score as well as the positive and negative subscale scores in the three RISPERDAL CONSTA groups compared to placebo (P<0.05).
• Clinical improvement occurred in significantly more patients in the RISPERDAL CONSTA groups versus those in the placebo group (P<0.001).
• According to the CGI, the RISPERDAL CONSTA groups had significantly greater improvements in mean scores from baseline to endpoint versus placebo (P<0.001) (Table: Efficacy Measures at Endpoint).

• Eighty percent (80%) to 83% of patients in the placebo and RISPERDAL CONSTA groups reported adverse events.
• The most common adverse events are listed in 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.

• Severity of EPS according to the ESRS was generally mild at baseline and did not change during the trial. ESRS total change scores from baseline to endpoint were −0.1, -1.5, 0.1, and 0 in the placebo and the RISPERDAL CONSTA 25-mg, 50-mg, and 75-mg groups, respectively. The incidence of spontaneously reported EPS was comparable between placebo (13%) and RISPERDAL CONSTA 25 mg (10%) but increased at higher doses of RISPERDAL CONSTA (24% and 29% in the 50- and 75-mg groups, respectively). Pairwise comparisons of each risperidone group with placebo were not significant.
• Antiparkinsonian medication was received by 13% of patients in the placebo group, 12% of patients in the RISPERDAL CONSTA 25-mg group, and 23% of patients in both the 50- and 75-mg groups.
• Mean weight changes at endpoint were as follows: placebo, -1.4 kg; 25 mg, 0.5 kg; 50 mg, 1.2 kg; 75 mg, 1.9 kg.
• According to patient ratings, injection site pain scores in all groups were low and decreased from an average of about 16 at the 1st injection to 10 at the 6th injection on a 100-point pain intensity scale. At the time of the sixth injection, investigators rated pain at the injection site as absent in 90% of patients in the placebo group and as absent in 80-84% of patients in the RISPERDAL CONSTA groups. Investigators rated swelling as absent in all patients after the sixth injection.
• No consistent abnormal results on the electrocardiogram or in vital signs were reported.

CLINICAL STUDIES – BIPOLAR I DISORDER

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.⁴

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.³

Monotherapy Treatment of Bipolar I Disorder

Quiroz et al (2010)⁴ presented Results from an international, randomized, double-blind, placebo (PBO)-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

• Additional inclusion criteria: ≥2 mood episodes (manic, mixed manic or depressed) during 2 years preceding enrollment (exclusive of current acute episode); 1 mood episode within 4 months of enrollment (stable patients only).
• Exclusion criteria included: >4 mood episodes/year in the 2 years before screening; DSM-IV-TR depressive episode, antisocial, or borderline personality disorder; unstable/serious medical illness; substance abuse in the 6 months preceding screening; chronic stimulant use in the 4 weeks preceding screening; depot antipsychotic use, other than RISPERDAL CONSTA; within 1 treatment cycle before screening; pregnant/nursing women.
• The study consisted of 5 periods:
  • Period I: Screening
  • Period II (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 III (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 3-week open-label oral risperidone phase were enrolled in a 26-week open-label RISPERDAL CONSTA stabilization phase at doses of 12.5-50 mg every two weeks.
  • Period IV (up to 24 months): Double-blind, Placebo-Controlled Withdrawal Phase
    • Stabilized patients maintaining a treatment response during the open-label stabilization phase entered a double-blind treatment phase and were randomized to either RISPERDAL CONSTA (at the dose received during the last eight 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.
  • Period V (8 weeks): Open-Label Extension
• Concomitant use of oral risperidone [first 3 weeks of period III 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 one 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
  • Young Mania Rating Scale (YMRS) score >12, CGI-S (Clinical Global Impressions-Severity) score >4, or MADRS (Montgomery Asberg Depression Rating Scale) score >12
  • Required an increase in RISPERDAL CONSTA dose or supplementation with oral risperidone

Results (Phase I-IV)

• Of the 559 patients who entered the study, 303 entered the double-blind phase (154 randomized to RISPERDAL CONSTA and 149 to 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 nine 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 maintained YMRS (P<0.001), MADRS (P=0.02), and CGI-S (P<0.001) 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% was experienced by 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 (one patient discontinued due to hyperglycemia) and 3% of patients in the placebo group (one patient discontinued due to weight increase) experienced glucose-related adverse events.
• Three patients died in the study, one during the open-label oral risperidone phase (perforated duodenal ulcer and peritonitis), and two during the open-label stabilization phase (accidental fall; chemical poisoning/completed suicide).
• Treatment-emergent EPS-related adverse events occurred in 3% of RISPERDAL CONSTA patients and 2% of placebo patients during period IV. There were two reports of tardive dyskinesia during the open-label risperidone phase, one of which led to discontinuation.

Adjunctive Treatment of Bipolar I 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 Disorder (type I or II) who relapse frequently (defined as at least four mood episodes in the past 12 months requiring psychiatric intervention). The two-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 type II population, the published Results focus on the type I population. Results from the total study population (type I and II) were presented in Macfadden et al (2011)⁵ and at the American Psychiatric Association Annual Meeting in 2006 (open-label stabilization: Kujawa et al [2006]⁶)

Study Design/Methods

• During the open-label phase, patients received RISPERDAL CONSTA 25 to 50 mg every two weeks (flexible dosing) in addition to TAU. TAU included treatment with antidepressants, mood stabilizers, or anxiolytics as determined by the investigator.
• During the first three weeks after RISPERDAL CONSTA initiation, patients continued their pre-existing 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 CGI-BP-S (Clinical Global Impressions for Bipolar Disorder - Severity) 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 NRC (nonremitted continuing) 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 one of the following:
  • Hospitalization for worsening of manic or depressive symptoms AND significant suicidal ideation determined by an ISST (InterSePT Scale for Suicidal Thinking) 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 GAF (Global Assessment of Functioning) 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 three patients assigned to RISPERDAL CONSTA plus TAU and one 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 one 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 experienced 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.
• No significant between-group differences were seen in electrocardiogram or laboratory Results, including changes for glucose levels and lipid panels.
• 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 two patients in the placebo plus TAU group died of motor vehicle accident and suicide.

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 22 April 2024.