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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

INVEGA SUSTENNA® (paliperidone palmitate)

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Clinical Trial Comparison

Last Updated: 06/18/2024

Summary

In a 13-week, international, multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group, flexible-dose schizophrenia study (n=1,214), the non-inferiority of INVEGA SUSTENNA to risperidone long-acting injection (RLAI) every 2 weeks was established. In this trial, the initiation regimen for INVEGA SUSTENNA was 234 mg on day 1 and 156 mg on day 8, both administered in the deltoid muscle.¹
In a 53-week, double-blind, randomized, parallel-group, multicenter schizophrenia study designed to assess the non-inferiority of INVEGA SUSTENNA (39, 78, 117, or 156 mg) to RLAI (25, 37.5, or 50 mg), both INVEGA SUSTENNA plus placebo (PBO) and RLAI plus oral risperidone improved mean Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint; however, INVEGA SUSTENNA was not found to be noninferior to RLAI. The INVEGA SUSTENNA initiation dosing regimen of 78 mg injections in the gluteal muscle on day 1 and day 8 may have led to low initial plasma levels of paliperidone, which resulted in INVEGA SUSTENNA not demonstrating noninferiority to RLAI.²^,³
In a 13-week, active-controlled, parallel-group, multicenter, open-label, rater-blinded, comparative study, the non-inferiority of INVEGA SUSTENNA (78, 156, or 234 mg) to RLAI (25, 37.5, or 50 mg) was established in adult Chinese patients with acute schizophrenia.⁴

DOSAGE STRENGTH INFORMATION

Doses of INVEGA SUSTENNA extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq to mg is 1.56.

INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

CLINICAL STUDIES

Clinical Trial Data

Trial Design	Results
DOUBLE-BLIND CLINICAL TRIALS
Pandina et al (2011)¹ conducted a 13-week, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter study assessing noninferiority of INVEGA SUSTENNA to RLAI in adult patients with schizophrenia (n=1,214, safety analysis set). *Treatment: Following a ≤7-day screening, washout, and tolerability period, patients were randomized to receive 1 of 2 treatments for a 13-week, double-blind period: INVEGA SUSTENNA* (n=606) Deltoid injection of INVEGA SUSTENNA 234 mg on day 1 followed by a 156-mg deltoid injection on day 8; thereafter, patients received flexibly dosed INVEGA SUSTENNA injections on days 36 (78 or 156 mg) and 64 (78, 156, or 234 mg) in either the deltoid or gluteal muscle. Oral supplementation with PBO was provided for days 1-28. Optional supplementation with PBO could be administered with each dose increase. PBO injections were matched to RLAI on day 8 and every 2 weeks thereafter. RLAI (n=608) RLAI 25 mg on days 8 and 22, followed by 25 or 37.5 mg on days 36 and 50; thereafter, patients received flexible doses of 25, 37.5, or 50 mg on days 64 and 78, all in the gluteal muscle. PBO injections matched those of INVEGA SUSTENNA on days 1, 8, 36, and 64. Oral supplementation was with flexible RIS (1-6 mg) for the first 28 days. Optional supplementation with RIS 1-2 mg could be administered with each dose increase.	Least-squares mean change in PANSS total score from baseline to endpoint was 0.4 (95% CI: -1.62, 2.38). As the lower limit of the 95% CI was greater than the pre-specified noninferiority margin of -5, INVEGA SUSTENNA was declared noninferior to RLAI. Least-squares mean change in CGI-S from baseline to endpoint was 0.0 (95% CI: -0.07, 0.17). Least squares mean change in PSP from baseline to endpoint was 0.2 (-1.22, 1.69). Both INVEGA SUSTENNA and RLAI showed similar improvements in SDS, positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Treatment response (≥30% reduction in PANSS total score) occurred in 53% of INVEGA SUSTENNA-treated patients and 48.5% of RLAI-treated patients (RR of INVEGA SUSTENNA vs RLAI, 1.1 [95% CI, 0.97, 1.25]). Plasma concentration-time profiles were similar between the INVEGA SUSTENNA and RLAI treatment groups. AEs occurring in ≥2% more of the INVEGA SUSTENNA-treated patients than of the RLAI-treated patients were insomnia (9.4% vs 6.7%), injection-site pain (5.1% vs 0.8%), and anxiety (4.3% vs 2.1%). Constipation occurred at an incidence that was ≥2% higher in RLAI-treated patients than in INVEGA SUSTENNA-treated patients (3.1% vs 0.8%). Post Hoc Analyses Additional post hoc analyses of the Pandina et al (2011) trial assessed the following outcomes: marked to severe illness⁵; recent diagnosis⁶; prior oAPs⁷; pain at injection site⁸
Fleischhacker et al (2008)², Fleischhacker et al (2011)³ conducted a 53-week, double-blind, randomized, parallel-group, multicenter study designed to assess the noninferiority of INVEGA SUSTENNA to RLAI with a nonoptimized dosing regimen (per-protocol analysis, n=570; safety analysis, n=747). *Treatment: INVEGA SUSTENNA* (n=379) Gluteal IM injection on days 1 and 8 (78 mg), followed by flexible doses of 39-156 mg every 4 weeks. Patients received PBO injections every month as well as oral PBO supplementation during the first 4 weeks of treatment and for up to 3 weeks after each dose increase. RLAI (n=370) PBO injection on day 1 and 25 mg RLAI on days 8 and 22, followed by flexible doses of 25, 37.5, or 50 mg RLAI administered every 2 weeks. Patients received supplementation with oral RIS (1–6 mg/day) during the first 4 weeks of treatment and for up to 3 weeks after every dose increase.	Median plasma concentrations of paliperidone in the INVEGA SUSTENNA group were consistently lower than those of the active moiety (risperidone +9-OH-risperidone/paliperidone) in the RLAI group from the first sample taken on day 64 until day 260. Least-squares mean change in total PANSS score was 2.6 points lower (95% CI: -5.84, 0.61) for RLAI than for INVEGA SUSTENNA. Since the lower bound of the 95% CI was -5.84, the predetermined margin for noninferiority (lower limit of the 95% CI) was not met. These results suggested that the dosing regimen used for INVEGA SUSTENNA needs to be adjusted to optimize plasma concentrations. The TEAEs that occurred in >10% of patients in either treatment group were insomnia (INVEGA SUSTENNA, 15%; RLAI, 15%), psychotic disorder (14%; 12%), worsening or relapse of schizophrenia (12%; 9%), anxiety (10%; 15%), headache (9%; 11%). The mean change from baseline to endpoint in body weight was -0.2 kg (baseline: 80.7 kg) in the INVEGA SUSTENNA group and 0.8 kg (baseline: 82.2 kg) in the RLAI group. Abnormally high prolactin levels during the double-blind phase occurred in 53% of men and 51% of women in the RLAI group, and in 31% of men and 42% of women in the INVEGA SUSTENNA group. The frequency of injection site pain was similar for both groups (2-3%).
OPEN-LABEL STUDIES
Li et al (2011)⁴ conducted a 13-week, randomized, active-controlled, parallel-group, multicenter, open-label, rater-blinded study assessing noninferiority of INVEGA SUSTENNA to RLAI in adult Chinese patients with acute schizophrenia (n=452, safety analysis set). *Treatment: Following a ≤7-day screening, washout, and tolerability period, patients were randomized to receive INVEGA SUSTENNA or RLAI: INVEGA SUSTENNA* (n=229) Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) with the optional injection site of the gluteal muscle for day 36 (78 or 156 mg) and day 64 (78, 156, or 234 mg). RLAI (n=223) Gluteal IM injection on days 8 and 22 (25 mg); flexible doses every 2 weeks; thereafter, patients received flexibly dosed RLAI injections days 36 and 50 (25 or 37.5 mg), days 64 and 78 (25, 37.5, or 50 mg). Oral RIS supplementation occurred during the first 4 weeks (1-6 mg/day). Additional oral RIS 1-2 mg/day was allowed during the 3-week period after each dosage increase.	INVEGA SUSTENNA was found to be noninferior to RLAI at endpoint because the lower limit of the 95% CI for the difference in least-squares mean between groups for the change in PANSS total score was greater than the protocol prespecified noninferiority margin of -5.5 (-2.3; 95% CI: -5.20, 0.63). Similar findings were also observed at each assessment point. Improvements from baseline to endpoint in CGI-S and PSP scores were similar between treatment groups. The responder rates (≥30% improvement in PANSS score) were 70.7% for INVEGA SUSTENNA and 78.4% for RLAI at endpoint. The most common TEAEs patients experienced in either treatment group were akathisia (INVEGA SUSTENNA, 13.1%; RLAI, 19.7%), tremor (10.5%; 17.9%), and insomnia. Mean increase in body weight and the percentage of patients experiencing significant (≥7%) weight increase from baseline to endpoint were similar between patients receiving INVEGA SUSTENNA (mean increase, 1.5 kg; percentage with ≥7% increase, 15.5%) and those receiving RLAI (1.5 kg; 17.3%). Prolactin-related AEs were also similar between the INVEGA SUSTENNA (n=19, 8.3%) and RLAI groups (n=20, 9%).
Abbreviations: AE, adverse event; AP, antipsychotic; CGI-S, Clinical Global Impression-Severity Scale; CI, confidence interval; IM, intramuscular; PANSS, Positive and Negative Syndrome Scale; PBO, placebo; PSP, Personal and Social Performance Scale; RIS, risperidone; RLAI, risperidone long-acting injection; RR, relative risk; SDS, Schedule for Deficit Syndrome; TEAE, treatment-emergent adverse event.

Two open-label pilot studies in schizophrenia comparing the effects of RLAI and INVEGA SUSTENNA on social⁹ and cognitive¹⁰ functioning and a long-term relapse prevention follow-up study of RLAI and INVEGA SUSTENNA ¹¹ have been referenced for your convenience.

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 20 May 2024.

References

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1	Pandina G, Lane R, Gopal S, et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):218-226.
2	Fleischhacker W, Gopal S, Samtani M, et al. Optimization of the dosing strategy for the long-acting injectable antipsychotic paliperidone palmitate: results of two randomized double-blind studies and population pharmacokinetic simulations. Poster presented at: The American College of Neuropsychopharmacology Annual Meeting; December 7-11, 2008; Scottsdale, AZ.
3	Fleischhacker WW, Gopal S, Lane R, et al. A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Int J Neuropsychopharmacol. 2012;15(1):107-118.
4	Li H, Rui Q, Ning X, et al. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1002-1008.
5	Fu DJ, Bossie CA, Sliwa JK, et al. Paliperidone palmitate versus risperidone long-acting injection in markedly-to-severely ill schizophrenia subjects: onset of efficacy with recommended initiation regimens. Clin Schizophrenia Relat Psychoses. 2014;8(2):101-109.
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8	Sliwa JK, Gopal S, Fu DJ, et al. Evaluating injection site pain with long-acting atypical antipsychotics using clinical trial databases of subjects with schizophrenia. Poster presented at: The 24th Annual U.S. Psychiatric and Mental Health Congress; November 7-10, 2011; Las Vegas, NV.
9	Koshikawa Y, Takekita Y, Kato M, et al. The Comparative Effects of Risperidone Long-Acting Injection and Paliperidone Palmitate on Social Functioning in Schizophrenia: A 6-Month, Open-Label, Randomized Controlled Pilot Trial. Neuropsychobiology. 2016;73(1):35-42.
10	Takekita Y, Koshikawa Y, Fabbri C, et al. Cognitive function and risperidone long-acting injection vs. paliperidone palmitate in schizophrenia: a 6-month, open-label, randomized, pilot trial. BMC Psychiatry. 2016;16(1):172.
11	Navarro PR, Romero Guillena SL, Gotor Sanchez LF, et al. The effectiveness of the long-acting injections of second generation antipsychotics: a 54-month follow-up study of risperidone long-acting injection vs paliperidone palmitate one-month formulation. Eur Psychiatry. 2018;48:S125-S126.