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INVEGA SUSTENNA® (paliperidone palmitate)

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Use of INVEGA SUSTENNA in Acute Schizophrenia

Last Updated: 11/11/2024

Summary

The efficacy and safety of INVEGA SUSTENNA as monotherapy in the treatment of adults with schizophrenia were assessed in the following pivotal studies: Four acute, short-term, fixed dose studies, one longer-term maintenance study and two long-term, open-label, flexible dose comparator trials with selected oral antipsychotic therapies.¹^-⁷
The initiation regimen for INVEGA SUSTENNA (234 mg/156 mg in the deltoid muscle on day 1/day 8) was designed to rapidly attain steady-state paliperidone concentrations when initiating therapy without the use of oral supplementation.⁸

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate 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. paliperidone, respectively.

ACUTE CLINICAL STUDIES

Acute Schizophrenia Clinical Trials

Trial Design		Results
Double-Blind Pivotal Trials
Pandina et al (2010)² conducted a 13-week, randomized, DB, parallel-group, multicenter, PBO-controlled, dose-response study evaluating three fixed doses of INVEGA SUSTENNA in patients with schizophrenia (n=636, ITT analysis set) Following a ≤7-day screening, washout, and tolerability period, patients were randomized to one of three INVEGA SUSTENNA treatment arms (39, 156, or 234 mg) or to PBO. Patients received initiation doses of 234 mg (all INVEGA SUSTENNA patients) or PBO on day 1 (deltoid IM injection) followed by their fixed doses or PBO on days 8, 36, and 64 (deltoid or gluteal IM injection).		Change in PANSS Total Score: INVEGA SUSTENNA 39 mg (n=155): -8.0 (P=0.034 vs PBO) INVEGA SUSTENNA 156 mg (n=161): -11.6 (P<0.001 vs PBO) INVEGA SUSTENNA 234 mg (n=160): -13.2 (P<0.001 vs PBO) PBO (n=160): -2.9 Estimated Effect Size Compared with PBO: INVEGA SUSTENNA 39 mg: 0.28 INVEGA SUSTENNA 156 mg: 0.49 INVEGA SUSTENNA 234 mg: 0.55 Onset of effect was seen as early as day 8 in the INVEGA SUSTENNA 39- and 234-mg groups and day 22 in the 156-mg group. Safety: Most common TEAEs (≥2% in any treatment group) that occurred more frequently (≥1% difference) in the total INVEGA SUSTENNA group than in the PBO group were injection-site pain (INVEGA SUSTENNA: 7.6% vs PBO: 3.7%), dizziness (INVEGA SUSTENNA: 2.5% vs PBO: 1.2%), sedation (INVEGA SUSTENNA: 2.3% vs PBO: 0.6%), pain in extremity (INVEGA SUSTENNA: 1.6% vs PBO: 0%), and myalgia (INVEGA SUSTENNA: 1% vs PBO: 0%). Post Hoc Analyses Additional post hoc analyses of the Pandina et al (2010) trial assessed the following outcomes: efficacy/tolerability following initiation dosing⁹; marked to severe exacerbations¹⁰; recent diagnosis¹¹; recent treatment with oral risperidone.¹²
Kramer et al (2010)⁵ conducted a 9-week, DB, randomized, international study assessing the safety and efficacy of two fixed INVEGA SUSTENNA doses compared to PBO in the treatment of schizophrenia (n=247) Following a 5-day screening/washout phase and a 7-day oral run-in period, patients were randomized to receive gluteal IM injections of INVEGA SUSTENNA doses (78 or 156 mg) or PBO without oral supplementation on days 1, 8, and 36.		Change in PANSS Total Score: INVEGA SUSTENNA 78 mg (n=63): -5.2 (P=0.001 vs PBO) INVEGA SUSTENNA 156 mg (n=68): -7.8 (P<0.001 vs PBO) PBO (n=66): 6.2 Safety: Incidence of TEAEs were similar between the treatment groups: PBO: 64% INVEGA SUSTENNA 78 mg: 65% INVEGA SUSTENNA 156 mg: 60%
Nasrallah et al (2010)¹ conducted a 13-week, multicenter, randomized, DB, PBO-controlled, parallel-group, dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA in patients with schizophrenia (n=514; ITT analysis set) Following a ≤7-day screening, washout, and tolerability period, patients were randomized to one of three fixed INVEGA SUSTENNA doses (39, 78, or 156 mg) or PBO administered by gluteal IM injection on days 1, 8, 36, and 64.		Change in PANSS Total Score: INVEGA SUSTENNA 39 mg (n=129): -13.6 (P=0.015 vs PBO) INVEGA SUSTENNA 78 mg (n=128): -13.2 (P=0.017 vs PBO) INVEGA SUSTENNA 156 mg (n=131): -16.1 (P<0.001 vs PBO) PBO (n=125): -7.0 Safety: AEs in at least 5% of patients in any treatment group were similar except for the following: weight increase (4% INVEGA SUSTENNA vs 0% PBO) somnolence (4% INVEGA SUSTENNA vs 1% PBO) A higher rate of serious TEAEs was reported for PBO-treated patients (18%) than for INVEGA SUSTENNA-treated patients (8-14%)
Gopal et al (2010)³ conducted a 13-week, multicenter, randomized, DB, PBO-controlled, parallel-group, dose-response study evaluating the efficacy and safety of three fixed doses of INVEGA SUSTENNA in patients with schizophrenia (n=349, primary efficacy analysis set). Following a washout, screening, and tolerability period that lasted for ≤7 days, patients were randomized to receive one of three fixed doses of INVEGA SUSTENNA (78, 156, or 234 mg) or PBO administered by gluteal IM injection on days 1, 8, 36, and 64.		Change from Baseline to Endpoint in PANSS Total Score (LOCF): INVEGA SUSTENNA 78 mg (n=93): -7.9 (P=0.19 vs PBO) INVEGA SUSTENNA 156 mg (n=94): -11.0 (P=0.019 vs PBO) INVEGA SUSTENNA 234 mg (n=30): -5.5 (no P-value vs PBO) PBO (n=132): -4.1 Differences from PBO in LSM Change in PANSS Total Score: INVEGA SUSTENNA 78 mg (n=93): -3.5 (P=0.19 vs PBO) INVEGA SUSTENNA 156 mg (n=94): -6.9 (P=0.019 vs PBO) INVEGA SUSTENNA 234 mg (n=30): no statistical comparison performed Safety: AEs occurring more frequently (≥5% difference) with INVEGA SUSTENNA than with PBO were headache, vomiting, injection-site pain, and pain in extremity
Additional Double-Blind Trials
Takahashi et al (2013)¹³ conducted a 13-week, randomized, DB, PBO-controlled trial assessing the safety and efficacy of INVEGA SUSTENNA in Asian patients with schizophrenia (N=323; mean age: 45 years; 57% male; baseline mean PANSS total score: 83.5-85.7). Dosing Schedule (all doses administered IM): INVEGA SUSTENNA (n=159): 234 mg on day 1 (deltoid); 156 mg on day 8 (deltoid); once-monthly injections of 117 mg (deltoid or gluteal) on days 36 and 64. PBO (n=164)	Efficacy Mean duration of INVEGA SUSTENNA and PBO exposure was 87 and 50 days, respectively. Compared to PBO, PANSS total scores significantly decreased from baseline to endpoint in the INVEGA SUSTENNA group (LSM [minus PBO]: -9.7; P<0.0001). More patients from the PBO vs INVEGA SUSTENNA group were classified as having a disease of “marked” severity or worse at endpoint (51.8% vs 39.2%, respectively). The percentage of treatment responders (≥30% reduction in PANSS total scores) was significantly higher in the INVEGA SUSTENNA vs PBO group (22.8% vs 8.5%; P=0.0005).-In addition, significant between group differences in baseline to endpoint CGI-S and PANSS Marder factor change scores favored INVEGA SUSTENNA over PBO. Safety The most frequently reported TEAEs for INVEGA SUSTENNA vs PBO, respectively were: insomnia (17%; 15.2%); injection site pain (13.2%; 6.7%); nasopharyngitis (12.6%; 6.1%); psychiatric symptoms (11.3%; 26.2%); EPS (10.1%; 4.9%) The incidence of serious TEAEs was higher for patients receiving PBO vs INVEGA SUSTENNA (15.2% vs 6.3%, respectively), as was the incidence of TEAEs leading to discontinuation (29.9% vs 17.0%). Mean PRL levels (ng/mL) remained stable at baseline and endpoint for men (30.57 vs 30.72, respectively) and slightly increased at endpoint for women (68.73 vs 79.36, respectively) in the INVEGA SUSTENNA group. For PBO, irrespective of gender, an overall decrease in mean PRL level was observed. One patient in the PBO group experienced a PRL-related TEAE (irregular menstruation). There were no clinically relevant changes in weight, waist circumference or BMI for either treatment group. However, more patients in the INVEGA SUSTENNA vs PBO group experienced a ≥7% increase in weight (9.4% vs 2.4%, respectively).
Pandina et al (2011)¹⁴ conducted a 13-week, randomized, DB, double-dummy, active-controlled, parallel-group, multicenter study assessing non-inferiority of INVEGA SUSTENNA to RLAI in adult patients with acute schizophrenia (n=1214, safety analysis set). Following a ≤7-day screening, washout, and tolerability period, patients were randomized to receive 1 of 2 treatments for a 13-week, DB 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.	LSM 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 non-inferiority margin of -5, INVEGA SUSTENNA was declared non-inferior to RLAI. LSM change in CGI-S from baseline to endpoint was 0.0 (95% CI: -0.07, 0.17). 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]). 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 illness¹⁵; recent diagnosis¹⁶; prior oAPs¹⁷; comparison to oral RIS¹⁸
Open-Label Studies
Parellada et al (2017)¹⁹ conducted a 6-week, multicenter, open-label, prospective observational study in hospitalized patients with acute schizophrenia from psychiatric units in Spain to evaluate the clinical effectiveness of INVEGA SUSTENNA monotherapy (n=61) and INVEGA SUSTENNA plus other APs (n=219). Dosing: Mean INVEGA SUSTENNA dose at baseline was 229.5 mg for monotherapy group and 229.0 mg for combination group; mean INVEGA SUSTENNA dose at discharge was 179.7 mg for monotherapy group and 186.9 for combination group. Most frequently used combination oAPs were PAL (22.83%) and RIS (16.42%).	Efficacy Significant mean reduction in CGI-SCH was observed in the overall population from baseline 4.7 (0.9) to final visit 3.3 (0.9); P<0.0001. Significant reduction in GCI-SCH observed with both INVEGA SUSTENNA monotherapy and INVEGA SUSTENNA plus other APs (P<0.0001 for both) Significant reduction in total mean BPRS score observed in both groups (P<0.0001 for both) Safety 20 (7.1 %) patients reported AEs with no cases of serious AEs
Li et al (2016)²⁰ conducted a 13-week, single-group, OL, prospective, noncomparative, multicenter study to evaluate the efficacy and tolerability of INVEGA SUSTENNA in hospitalized Asian patients with an acute exacerbation of schizophrenia (ITT: n=212; mean age: 37.1 years). Dosing: Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections of 117-234 mg (deltoid IM or gluteal IM) administered on days 36 and 64. Mean maintenance dose after day 8: 178.6 mg; mean duration of exposure: ≥92 days (29.7%); 64-91 days (49.1%); 36-63 (8.0%); 8-35 days (9.0%); ≤7 days (4.2%) Concomitant medications included, oral atypical APs (27.8%; primarily RIS and PAL) and oral typical APs (16.1%).	Efficacy Significant improvements were observed in mean PANSS total change scores at day 4 (-6.1; P<0.001) through to week 13 (-23.9; P<0.001). Excluding patients who received concomitant antipsychotics after day 1 (n=64), mean change in total score from baseline to day 4 and week 13 was -5.6 (P<0.001) and -21.9 (P<0.001), respectively. Safety Most common TEAEs (>5%): hyperprolactinemia^a (11.8%); constipation (9.0%); nasopharyngitis (8.5%); insomnia (8.0%); weight increased (7.5%); and tremor (5.2%) Four patients experienced serious treatment-related TEAEs (sinus bradycardia [1.4%]; worsening of schizophrenia [0.5%]). The most common (≥2%) EPS-related TEAEs included: tremor (5.2%); akathisia (4.7%); EPS (3.3%); and dystonia (2.4%) Sixteen women (15.4%) and thirteen men (12.0%) reported PRL-related TEAEs. A significant weight gain (≥7 increase from baseline) was observed in 14.6% patients while a significant weight loss (≥7 decrease from baseline) was observed in 2.8% of patients.
Hargarter et al (2015)²¹ conducted a 6-week, international, non-interventional, multicenter, observation study examining the efficacy and safety of INVEGA SUSTENNA in 367 patients (mean age: 39.8 years; 65.9% male) admitted to the hospital for an acute exacerbation of schizophrenia. Dosing: Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections of 78-234 mg (deltoid IM or gluteal IM).	Efficacy Significant improvements in BPRS total scores were observed as early as day 8 and continued through to endpoint (baseline: 50.2; endpoint: 30.8; P<0.0001). CGI-S scores significantly improved beginning at day 8 through to endpoint (baseline: 3.7; endpoint: 2.3; P<0.0001). According to the CGI-C scale, 93.5% of patients were minimally, much or very much improved from baseline to endpoint. Safety TEAEs, primarily mild to moderate in intensity, reported in ≥2% of patients, were tremor (2.5%) and schizophrenia (2.2%). From baseline to endpoint, the mean ESRS total score significantly decreased (mean change: -1.7; P<0.0001). Mean change in body weight and BMI from baseline to endpoint was 0.95 kg and 0.32 kg/m², respectively.
Si et al (2015)²² conducted a 13-week, OL, multicenter prospective study examining the efficacy and safety of INVEGA SUSTENNA in Chinese patients with acute schizophrenia (safety analysis set: n=616; full analysis set: n=610 [mean age: 31.5 years; 55.1% male]). Dosing: Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections of 117-234 mg (deltoid IM or gluteal IM) administered on days 36, 64 and 92. Mean INVEGA SUSTENNA dose: 179 mg; Mean duration of exposure: 94 days. Most commonly received concomitant medications (>5 patients) included: RIS (35.2%), trihexyphenidyl hydrochloride (22.1%), herbal preparation (13.3%), lorazepam (11.6%), clonazepam (9.7%), PAL (9.5%), OLA (8.9%), and QUE (6.7%).	Efficacy A ≥30% decrease in PANSS total score from baseline to week 13 was achieved in 443 patients (72.6%). The PANSS total score significantly improved from baseline to week 13 (-9.7 to -30.9, respectively; P<0.001). Safety Most common (>2% incidence) TEAEs: EPS (8.4%); insomnia (4.7%); constipation (4.4%); URI (4.1%); and akathisia (2.3%). During the study one death was reported. The most common EPS-related TEAE categories included: parkinsonism (8.9%) followed by hyperkinesia (2.9%), dystonia (0.3%), tremor (0.3%), and dyskinesia (0.2%). Nine patients experienced PRL-related TEAEs; 5 had increased PRL levels, 2 women had delayed menses and 1 patient each had oligomenorrhea, irregular menstruation and menstrual disorder. A significant weight gain (≥7 increase from baseline) was observed in 7.8% of patients while a significant weight loss (≥7 decrease from baseline) was observed in 2.6% of patients.
Hargarter et al (2014)²³ reported results in patients with acute schizophrenia switched from oral antipsychotics (ITT, n=212). Study Design PALMFlex is an international, prospective, 6-month, OL study conducted to assess the efficacy and safety of treatment with flexibly dosed INVEGA SUSTENNA in adult patients with acute or nonacute schizophrenia who failed previous treatment with other antipsychotics. Following a ≤4 week screening, washout and tolerability period, patients were administered IM (deltoid) INVEGA SUSTENNA 234 mg on day 1 and 156 mg on day 8 (±2 days) upon an acute exacerbation of schizophrenia. Subsequently, monthly injections of INVEGA SUSTENNA were given on days 38, 68, 98, 128 and 158 (±7 days) using flexible maintenance dosages within the range of 78-234 mg. Exclusions: Clozapine use within 3 months	Efficacy Patients transitioned from oral antipsychotics primarily due to lack of efficacy (45.8%) and lack of compliance (34.9%). Patients received a mean modal INVEGA SUSTENNA maintenance dose of 168 mg for a mean treatment period of 136.9 days. Overall, 66.7% of patients experienced a ≥30% improvement in PANSS total scores from baseline to LOCF endpoint while 43.5% of patients achieved a ≥50% improvement. From baseline to LOCF endpoint, significant improvements were observed in mean PANSS total (-31.0; P<0.0001) and mean CGI-S (-1.5; P<0.0001) scale scores. Significant reductions in PANSS total were observed as early as day 8. Based on CGI-S scale scores, the proportion of patients rated markedly ill or worse decreased from 75.1% at baseline to 20.5% at LOCF endpoint Safety At least one TEAE was experienced in 63.7% of patients with the majority rated mild-to-moderate in nature by investigators (89.1%). The most common TEAEs (≥5%) were injection site pain (13.7%), insomnia (10.8%), psychotic disorder (10.4%), headache (6.1%) and anxiety (6.1%). Potentially prolactin-related TEAEs occurred in 5.7% of the total patient population. Mean ESRS total scores, while low at baseline, significantly declined during the trial (3.8 baseline to 2.3 LOCF endpoint; P<0.0001). Mean changes in baseline to LOCF endpoint weight and BMI change were 2.6 kg and 0.9 kg/m², respectively. Forty patients (22.5%) experienced a ≥7% increase in body weight.
Li et al (2011)²⁴ conducted a 13-week, randomized, active-controlled, parallel-group, multicenter, OL, rater-blinded study assessing non-inferiority of INVEGA SUSTENNA to RLAI in adult Chinese patients with acute schizophrenia (n=452, safety analysis set). 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: 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 non-inferior to RLAI at endpoint because the lower limit of the 95% CI for the difference in LSM mean between groups for the change in PANSS total score was greater than the protocol prespecified non-inferiority 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; ARI, aripiprazole; BMI, body mass index; BPRS, Brief Psychiatric Rating Scale; CGI-C, Clinical Global Impression-Change Scale; CGI-S, Clinical Global Impression-Severity Scale; CGI-SCH, Clinical Global Impression-Schizophrenia; DB, double-blind; ESRS, Extrapyramidal Symptom Rating Scale; HAL, haloperidol; HR, hazard ratio; IM, intramuscular; ITT, intent-to-treat; LOCF, last observation carried forward; LSM, least-squares mean; oAPs, oral antipsychotics; OL, open-label; OLA, olanzapine; PAL, paliperidone ER; PANSS, Positive and Negative Syndrome Scale; PBO, placebo; PRL, prolactin; PSP, Personal and Social Performance Scale; QUE, quetiapine; RIS, risperidone; RLAI, risperidone long-acting injection; RR, relative risk; TEAE, treatment-emergent adverse event; URI, upper respiratory tract infection. ^aHyperprolactinemia TEAEs also included the preferred terms “blood prolactin increased” and “blood prolactin abnormal”. Each patient is counted only once within each system organ class and within each preferred term.

other relevant literature

A randomized, 13-week study evaluating the efficacy and metabolic effects of INVEGA SUSTENNA and olanzapine in Han Chinese patients with first-episode schizophrenia is referenced for your convenience.²⁵

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 October 2024.

References

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