RISPERDAL CONSTA®

(risperidone long acting injection)

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RISPERDAL CONSTA® (risperidone long acting injection)

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Use of RISPERDAL CONSTA in the Elderly

Last Updated: 07/02/2024

Summary

RISPERDAL CONSTA dosing recommendations are the same for otherwise healthy elderly and nonelderly patients with schizophrenia. The recommended starting dose is 25 mg intramuscularly every 2 weeks. Oral RISPERDAL^® (or another antipsychotic medication) should be given with the first injection of RISPERDAL CONSTA^® and should be continued for 3 weeks.¹
A subgroup analysis was performed in 52 clinically stable patients ≥65 years with schizophrenia or other psychotic disorders from a 6-month, open-label study of RISPERDAL CONSTA every 2 weeks. There were significant improvements in clinical symptoms, overall functioning, and patient satisfaction. The most common adverse events were parkinsonism, extrapyramidal disorder, tremor, depression, diarrhea, dizziness, and insomnia.²
A post hoc analysis of an open-label, international, multicenter study included fifty-seven clinically stable, elderly patients (≥65 years old) with schizophrenia or schizoaffective disorder received RISPERDAL CONSTA every 2 weeks for up to 12 months. Treatment was well tolerated, and the most common adverse events reported were insomnia, constipation, bronchitis, psychosis, and rhinitis. In addition, there was a statistically significant decrease from baseline to endpoint in the mean PANSS (Positive and Negative Syndrome Scale) total score.³

PRODUCT LABELING

WARNING: Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL CONSTA^® is not approved for use in patients with dementia-related psychosis.

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS, and CLINICAL PHARMACOLOGY.

CLINICAL DATA

Open-Label Trials

Open-Label, Flexible-Dose, Naturalistic Observational Study

Suzuki et al (2012)⁴ conducted an 24-week, open-label, flexible-dose, naturalistic observational study of 48 Japanese patients with schizophrenia. Patients on a stable oral risperidone dose for at least 6 months were switched to RISPERDAL CONSTA monotherapy due to poor symptom control or side effects. Patients receiving RISPERDAL CONSTA 25 mg every 2 weeks in addition to their previous therapeutic medications. After 4 weeks, previous therapeutic medications were titrated down with supplementation of RISPERDAL CONSTA equivalent doses. By week 8, all patients transitioned to a patient specific optimized dose of RISPERDAL CONSTA monotherapy. RISPERDAL CONSTA patients were stratified into 2 groups: an older group aged ≥60 years (mean age 64.6 years, n=18) or a younger group aged <60 years (mean age 45.4 years, n=13). A control group of older patients (mean age 63.8 years, n=17) continued to receive oral risperidone.

There were no significant differences in clinical symptom improvement between the older and younger RISPERDAL CONSTA groups and the control group (see Clinical Symptoms Assessments at Baseline and Change at Endpoint).

Clinical Symptoms Assessments at Baseline and Change at Endpoint⁴

	Control group (n=17)		Older group (n=18)		P-value	Younger group (n=13)		P-value versus older group
	Baseline	Change from baseline to 24 weeks	Baseline	Change from baseline to 24 weeks	P-value	Baseline	Change from baseline to 24 weeks	P-value versus older group
PANSS total	95.7	-12.6^a	96.8	-16.5^a	0.23	92.8	-12.8^a	0.32
CGI-S	5.1	-0.3	4.9	-0.9^a	0.008	5.2	-1.2^a	0.16
Abbreviations: CGI-S, Clinical Global Impression-Severity of Illness Scale; PANSS, Positive and Negative Syndrome Scale. ^aP<0.005 versus baseline.

The mean changes from baseline of Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) total score and prolactin level were significantly greater in the older group compared to the control group. Changes in body weight and BMI were small in all groups. The total cholesterol and triglyceride levels showed no significant differences among the groups (see Table: Safety Assessments at Baseline and Change at Endpoint).

Safety Assessments at Baseline and Change at Endpoint⁴

	Control group (n=17)		Older group (n=18)		P-value versus younger group	Younger group (n=13)		P-value versus older group
	Baseline	Change from baseline to 24 weeks	Baseline	Change from baseline to 24 weeks	P-value versus younger group	Baseline	Change from baseline to 24 weeks	P-value versus older group
DIEPSS total score	7.5	-0.5	6.9	-3.1^a	<0.0001	6.2	-3.6^a	0.48
Body weight (kg)	54.3	-0.1	58.0	-1.4	0.11	68.2	-1.1	0.84
BMI (kg/m²)	21.4	-0.0	22.2	-0.6	0.20	24.0	-0.4	0.84
Total cholesterol (mg/dl)	183.8	-5.3	191.5	-16.8	0.10	175.6	-12.2	0.66
Triglycerides (mg/dl)	91.8	-5.9	128.9	-30.1^a	0.07	139.0	-24.1	0.74
Prolactin (mg/ml)	50.8	5.5	45.4	-6.7^a	0.0005	50.0	-11.2^a	0.41
Abbreviations: BMI, Body Mass Index; DIEPSS total score, Drug-Induced Extrapyramidal Symptoms Scale. ^aP<0.05 versus baseline.

The mean change in risperidone, biperiden, diazepam equivalent doses and doses of sennoside were significantly decreased from baseline in both the older and control group.

Subgroup analysis from the Switch to Risperidone Microspheres (StoRMi) Study

Kissling et al (2007)² performed a subgroup analysis in patients aged ≥65 years from the Switch to Risperidone Microspheres (StoRMi) study. This 6-month, open-label study investigated the long-term efficacy and safety of RISPERDAL CONSTA in clinically stable patients who required a change of antipsychotic treatment. Moller et al (2005)⁵ published the overall efficacy and safety results from all patients.

The transition to RISPERDAL CONSTA occurred without an oral risperidone run-in, but the previous antipsychotic therapy was continued for 3 weeks. The recommended starting dose of RISPERDAL CONSTA was 25 mg every 2 weeks given intramuscularly as a gluteal injection. However, higher doses (37.5 mg or 50 mg) could have been initiated and dose adjustments were permitted.

The elderly analysis included 52 patients with an average age of 71 years (range: 65-89) and 64% were female. DSM-IV diagnoses included schizophrenia (71%), schizoaffective disorder (14%), schizophreniform disorder (2%), or other psychiatric disorders (14%). The study completion rate was 81%. The reasons for discontinuation were adverse events (n=6), withdrawal of consent (n=3), and death (n=1). While most patients received 25 mg as the initial dose (89%), at endpoint 60%, 26%, and 14% of patients were on 25 mg, 37.5 mg, and 50 mg every 2 weeks, respectively.

There was a mean improvement in PANSS total scores from baseline to endpoint of 15.8±19.9 points. Significant improvements from baseline in PANSS total scores were also observed at month 1, 3, and 6 (P=0.0001). At study endpoint 47% of patients had a ≥20% improvement in the PANSS total score versus baseline. Statistically significant improvements from baseline (month 1, 3, 6, and endpoint, P<0.001) were also seen on the PANSS positive, negative, and general psychopathology subscales as well as in all five Marder symptom factors (positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression). Significant improvements (P<0.001) from baseline to endpoint were also observed on the CGI-S (Clinical Global Impressions-Severity), GAF (Global Assessment of Functioning), and patient satisfaction scale. Quality of life was measured by the SF-36 (Medical Outcome Survey Short Form) and reported statistically significant improvements from baseline to endpoint in the role-physical, social functioning, role-emotional, and mental health components.

The most common adverse events (>5%) were parkinsonism, extrapyramidal disorder, tremor, depression, diarrhea, dizziness, and insomnia. Serious treatment-emergent adverse events were reported by 11 patients and two suicide attempts and exacerbation of disease were considered related to treatment. There was one case of new onset diabetes mellitus and no cerebrovascular adverse events were reported. In total extrapyramidal treatment-emergent adverse events were reported by 19.2% of patients. The severity of movement disorders as measured by mean ESRS (Extrapyramidal Symptom Rating Scale) total score and the Parkinsonism subscale, were significantly improved (P≤0.001) from baseline to endpoint.

Lasser et al (2004)³ conducted a post hoc analysis of elderly patients (n=57, ≥65 years) from an open-label, 1-year, international (Europe and Canada), multicenter trial designed to examine the long-term safety and efficacy of RISPERDAL CONSTA in 725 stable patients with schizophrenia or schizoaffective disorder. Fleischhacker et al (2003)⁶ published the results of all patients with schizophrenia.

All patients had been receiving a stable dose of an antipsychotic for at least 4 weeks at study entry. Doses of RISPERDAL CONSTA were assigned according to clinician judgment and previous risperidone dose and could be adjusted as needed during the trial. The following concomitant medications were permitted during the study: medications prescribed for sleep, antiparkinsonian agents, antidepressants, mood stabilizers, propranolol for akathisia, and benzodiazepines for agitation and insomnia. Efficacy assessments included the PANSS, the CGI scale, and Quality of Life measures using the SF-36. Safety and tolerability assessments included spontaneously reported adverse events, the ESRS for extrapyramidal symptoms, electrocardiogram, patient weight, patient ratings of injection-site pain, and investigator ratings of injection-site pain, redness, swelling, and induration.

Trial Design

Run-in	Open-Label Period	Number of elderly patients
2 weeks	Weeks 1–50 (oral supplementation for 2–3 weeks); intramuscular route of administration	Number of elderly patients
Discontinuation of previous antipsychotic and initiation of oral risperidone 1-6 mg/day	RISPERDAL CONSTA 25 mg q 2 weeks RISPERDAL CONSTA 50 mg q 2 weeks RISPERDAL CONSTA 75 mg q 2 weeks	n=27 n=21 n=9

The average age of the 57 elderly patients was 70.9 years and 53% were female. The majority of patients had a diagnosis of schizophrenia (86%) versus schizoaffective disorder (14%). Mode dose was used to group patients for analysis. Results for patients in the 75 mg group were not presented separately due to the small number of patients in this group (n=9) and are instead included in the combined group (i.e., patients receiving 25 mg, 50 mg, and 75 mg of RISPERDAL CONSTA). Mean duration of treatment was 237, 234, and 254 days in the RISPERDAL CONSTA 25, 50, and 75 mg groups, respectively. Premature discontinuation was seen in thirteen patients (23%) of the study group and included withdrawal of consent in six patients, adverse events in two patients, and other reasons in five patients.

There was a statistically significant decrease from baseline in mean PANSS total score at endpoint in all three RISPERDAL CONSTA treatment groups (25 mg, 50 mg, and combination) (see Mean PANSS Total Scores at Baseline and Change at Endpoint).

Mean PANSS Total Scores at Baseline and Change at Endpoint (patients ≥65 years old)

	RISPERDAL CONSTA
	25 mg (n=27)	50 mg (n=21)	Combined treatment group (n=57)
Average PANSS total at baseline	71.3 ± 3.4	76.2 ± 2.1	73.0 ± 2.1
Change in PANSS total at endpoint	-8.8 ± 1.5	-13.6 ± 2.4	-10.5 ± 1.5
P-value	P<0.001	P<0.001	P<0.001

Scores on each of the five PANSS factors (positive symptoms, negative symptoms, uncontrolled hostility/excitement, disorganized thoughts, and anxiety/depression) decreased significantly from baseline in the RISPERDAL CONSTA 50 mg and combined treatment groups and on four of the five factors in the 25 mg group. There was a significant decrease in the PANSS uncontrolled hostility/excitement scores in the 50 mg and combined treatment groups (P<0.01), but not in the 25 mg group. Clinical improvement, defined as ≥20% reduction in PANSS total scores, was achieved by 42%, 62%, and 49% of patients in the RISPERDAL CONSTA 25 mg, 50 mg, and the combined treatment groups respectively. Symptom improvements were similar in the elderly patients (≥65 years) and in the younger patients (<65 years) in this trial.

The proportion of patients rated on the CGI severity scale as not ill or with very mild or mild illness increased from 28% at baseline to 69% at endpoint. At endpoint, no patients were rated as being marked to severely ill compared to 14% at baseline. Improvement of at least 1 point in CGI scores from baseline to endpoint occurred in 37%, 76%, and 55% of patients in the 25 mg, 50 mg, and combined treatment groups, respectively.

Quality of life improvements were noted on each of the ten subscales of the SF-36 scale. There were significant mean score increases in the total patient group on the standardized mental component scale (+ 4.6, P<0.05), vitality (+ 6.1, P<0.05), social functioning (+ 9.6, P<0.01), and role emotional (+ 14.7, P<0.05).

Safety data was available for all of the elderly patients (n=57). There was a significant decrease in ESRS total scores from baseline to endpoint in the combined treatment group (P<0.001). Mean ESRS subscale scores were unchanged or improved at endpoint in the combined treatment group. Adverse events were reported by 74% of the RISPERDAL CONSTA combined group, 74% of the 25 mg group, 71% of the 50 mg group, and by 78% of the 75 mg group. No cases of emergent tardive dyskinesia were reported. Adverse events reported in >10% of patients were insomnia (14%), constipation (12%), psychosis (11%), rhinitis (11%), and bronchitis (12%). The incidence of adverse events was not dose related. There were no clinically significant changes in laboratory findings, electrocardiograms, and vital signs reported. In the elderly group, the average increase in body weight was 0.3 kg at endpoint. On a visual analog scale (out of a possible 100), patient ratings of injection-site pain decreased significantly from baseline to endpoint. Scores were reduced from 8.6 ± 2.2 after the first injection to 2.3 ± 0.6 at endpoint (P<0.01). After the first injection of RISPERDAL CONSTA, physician’s assessments reported pain in eight patients (mild=5, moderate=3), induration in two patients (mild=1, moderate=1), swelling in one (mild), and redness in no patients. At Week 48, physician assessment of injection pain was mild in 5 patients with no induration, swelling, or redness.

Gharabawi et al (2003)⁷ assessed the incidence of emergent tardive dyskinesia as well as the effect of existing symptoms of dyskinesia and other movement disorders in elderly patients treated with RISPERDAL CONSTA. See the description above (Lasser et al [2004])³ for information regarding study design and patient population. Fifty-seven (n=57) stable elderly patients with schizophrenia or schizoaffective disorder were included in the analysis of a 1-year, open-label trial.

The incidence of tardive dyskinesia was determined according to the criteria proposed by Jeste et al (2000)⁸ while dyskinesia was measured using the ESRS 7-item dyskinetic movement subscale (lingual, jaw, buccolabial, truncal, choeroathetoid movements, and other involuntary movements) at months 1, 2, 3, 6, 9, and 12. Each item on the ESRS is rated from 0=absent to 6=severe and constant. Dyskinesias were classified as follows in Dyskinesia Classification.

Dyskinesia Classification

Classification	Eligible Patients	Definition
*Dyskinesia at baseline*	Patients with dyskinesia noted at baseline	Score ≥3 on one item or a score ≥2 on two items of the ESRS dyskinetic movement subscale
*Resolved baseline dyskinesia*	Patients with dyskinesia noted at baseline	Score improvement at endpoint that resulted in no longer meeting criteria for baseline dyskinesia.
*Emergent tardive dyskinesia*	Patients without dyskinesia at baseline	Increase from baseline ≥3 points on one item or an increase of ≥2 points on two items of the ESRS dyskinetic movement subscale at any time point
*Persistent tardive dyskinesia*	Patients without dyskinesia at baseline	Emergent tardive dyskinesia on two or more consecutive visits

Of the 57 elderly study subjects, 44 patients (77.2%) completed the trial. The most common reasons for discontinuation were withdrawal of consent (n=6) and adverse event (n=2). The majority of patients (84%) had received the 25 or 50 mg dose of RISPERDAL CONSTA. Mean duration of exposure was 259 and 216 days for female and male patients, respectively.

Fifty-five patients had baseline ESRS data and at least one post-baseline assessment. Among all elderly patients (male and female), mean ESRS scores were improved or unchanged from baseline after treatment with RISPERDAL CONSTA. Overall subjective mean ESRS score decreased by -1.4 at endpoint from 4.0 at baseline (P=0.01). Mean ESRS parkinsonism scores decreased by -3.6 at endpoint from 10.6 at baseline (P<0.001), and mean ESRS dyskinesia scores decreased by -0.6 at endpoint from 2.75 at baseline (P=0.064). Dystonia and akathisia scores were low at baseline and endpoint evaluations for both male and female patients.

There were 42 patients without dyskinesia at baseline, and none of these patients developed emergent tardive dyskinesia during the trial. Thirteen patients had dyskinesia at baseline (7 female, 6 male). Prior antipsychotic treatment of the 13 patients who had dyskinesia at baseline was conventional depots (n=5), antipsychotic polytherapy (n=4), risperidone (n=2), olanzapine (n=1), and haloperidol (n=1). Among these patients, the mean ESRS dyskinesia score decreased by -2.4 at endpoint (mean baseline value = 10.4) (P=0.059). Individually, according to ESRS scores at baseline versus endpoint, nine patients (4 female, 5 male) improved (score reduction of -1 to -10) and 4 patients (3 female, 1 male) worsened (score increase of +1 to +2). Of the nine patients who improved, five patients (2 female, 3 male) were classified as having baseline dyskinesia resolved at endpoint.

Among all patients, significant improvement in PANSS total scores was noted at all time points. See the description above (Lasser et al [2004])³ for further information regarding efficacy in the elderly patients.

Retrospective Reviews

Trial Design	Results
Gopal et al (2011)⁹ conducted a post-hoc analysis of randomized, double-blind clinical studies and post-marketing surveillance reports to determine the risk of cardiovascular morbidity and sudden death due to cardiac causes in patients treated with oral and LAI RIS or PAL compared to placebo. The analysis consisted of 64 placebo- and active-controlled studies including 11,096 patients (mean age: 44 years). RIS-treated patients included in the analysis had a diagnosis of either dementia (34%), schizophrenia (33%), bipolar I disorder (23%), disruptive behavior/conduct disorder (6%), autistic disorder (3%), schizoaffective disorder (1%), or were healthy participants (27.2%). The mean modal injection dose of RIS was 41.1 mg with a median treatment duration of 42 days. Outcomes measured included medically important treatment-emergent adverse events prior to cardiovascular death, which consisted of cerebrovascular disorders, and changes in QT interval.	Pooled data for RIS (oral/LAI) and PAL: There was a significantly higher risk of cerebrovascular events in the RIS/PAL group compared to placebo (odds ratio (OR): 3.7 [95% CI: 2.2, 6.4]). The OR for cerebrovascular disorders was numerically higher for elderly (3.8) versus non-elderly (3.7) patients and for patients without previous cardiovascular disease history versus those with a cardiovascular disease history (5.5 vs. 2.7, respectively). The point estimate for the OR was numerically greater in elderly vs. non-elderly patients for all CV events, except ischemic heart disease. A greater proportion of elderly patients (age >74 years) treated with RIS/PAL had maximum QTcF increase of between 30-60 ms and >60 ms from baseline, vs. younger age categories (age <30 and age 30-74 years old). Post-marketing experience with RIS (oral/LAI): Three hundred-ninety-eight fatal outcomes related to torsade de pointes/QT prolongation were identified: sudden cardiac death (n=166); cardiac arrest (n=151); cardio-respiratory arrest (n=31); QT prolongation (n=18); sudden cardiac death (n=11); ventricular tachyarrhythmia (n=4); torsade de pointes (n=3). In the majority of RIS cases (98%; n=390/398) confounding medical history, confounding concomitant medication(s), completed suicide/overdose, insufficient documentation, improbable latencies, or other causes of death were reported. There was insufficient evidence to support a clear drug-event association in the remaining 8 cases.
Scott et al (2011)¹⁰ conducted a retrospective chart review (January 2006 to July 2008) study to evaluate the effect of atypical antipsychotic medication on clinical symptom relief in older patients diagnosed with VLOSLP (very late onset schizophrenia-like psychosis) including schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, delusional disorder, or psychosis not otherwise specified (N=21). Patients included those prescribed atypical antipsychotic medications if they met the criteria for VLOSLP: presence of psychosis as defined by either delusions or hallucinations, formal thought disorder, or catatonic-like stupor, and onset of such symptoms at 60 years of age or more.	Of the 8 outpatients and 13 inpatients treated with atypical antipsychotic medications and meeting the criteria for VLOSLP, one inpatient was treated with RLAI The patient (female, 82 y.o.) was reported to have improved from an initial severity of symptoms described as “severe' to a treatment response rating of “good” at discharge.
Tadger et al (2008)¹¹ conducted a retrospective chart review (January to December 2006) of elderly patients (N=25; mean age: 72 years; 28% male) to assess remission in elderly patients with schizophrenia treated with RLAI over a one-year period; patients had previously undergone treatment with typical or atypical antipsychotics. Discontinuation of previous medication was due to non-adherence (60%) and adverse events (28%). Primary assessment was remission status in patients receiving RLAI. Remission was defined as a score of ≤3 (1=absent; 2=minimal; 3=mild) for each of the following 8-items for a period of at least 6 months: delusions, hallucinations, conceptual disorganization, affect, conversation, social withdrawal, mannerism, and thought content.	After six months of treatment with RLAI, the mean dose was 36 mg every 2 weeks. Nineteen patients (76%) were adherent to treatment during the one-year study period Fifteen patients (60%) had scores of ≤3 on all eight remission items for a period of at least 6-months. At baseline, 8 patients were rated as markedly ill on the CGI scale, while 15 were rated as severely ill, and two as extremely ill. After one-year of treatment, 9 patients were very much improved on the CGI scale, while 10 were much improved. Four patients (16%) discontinued treatment due to a lack of positive response. The authors concluded that the use of RLAI improves chances to achieve remission in elderly patients with schizophrenia.
Singh et al (2007)¹² conducted a retrospective chart review (N=18) of elderly patients aged 66-84 (mean age 70.5 years) living in Australia. Patients had a diagnosis of schizophrenia/ schizoaffective disorder (17/18) or Alzheimer's disease (1/18). Fourteen patients were previously administered RLAI for an average of 17.2 months (range 3-38 months) RLAI: 25 mg every two weeks; 15 patients received a cross-titration of oral RIS 1-2 mg/day over 2-4 weeks. Doses of RLAI were adjusted as needed; final dosage treatments were: 12 patients received 37.5 mg every 2 weeks, three patients received 50 mg every 2 weeks, one patient received 75 mg every 2 weeks, one patient received 37.5 mg every 4 weeks, and one patient continued on 25 mg every 2 weeks.	Patients reported some improvement of symptoms and four patients became free of all positive and negative symptoms. Adverse events included parkinsonism, akathisia, sedation, weight gain, and a transient ischemic attack. One male and six females with a history of EPS on prior treatments showed improvement in symptoms. One patient with Alzheimer's disease did not report any adverse events and his symptoms improved; this patient transitioned to RLAI and another medication for cognition.
Abbreviations: LAI, long-acting injectable; PAL, paliperidone; RIS, risperidone; RLAI, risperidone long-acting injection

Other Relevant Literature

Several additional publications including case reports describing the use of RISPERDAL CONSTA in elderly patients have been referenced.¹³^-²⁰

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 11 June 2024.

References

Show

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8	Jeste DV, Okamoto A, Napolitano J, et al. Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone. Am J Psychiatry. 2000;157(7):1150-1155.
9	Gopal S, Hough D, Karcher K, et al. Risk of cardiovascular morbidity with risperidone or paliperidone treatment: analysis of 64 randomized, double-blind trials. J Clin Psychopharmacol. 2013;33(2):157-161.
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