Summary

• BOXED 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. INVEGA SUSTENNA is not approved for use in patients with dementia-related psychosis.¹ Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (CV; eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature.²
• Pivotal Randomized Clinical Trials: Few deaths were reported during pivotal clinical trials with paliperidone palmitate. Causality was assessed in some of the cases. Details are provided in the Table: Paliperidone Palmitate Pivotal Clinical Trial Mortality Results.
• Meta-Analyses:
  • In a systematic review and random-effects meta-analysis of prospective and retrospective studies assessing mortality risk in patients with schizophrenia versus the general population, second-generation long-acting injectable antipsychotics (SGA-LAIs) were protective against all-cause mortality versus no antipsychotic use (risk ratio [RR]=0.39).³
  • In a series of meta-analyses assessing the effect of long-acting injectable antipsychotics (LAI-APs) on mortality in patients with schizophrenia, no significant difference was observed between LAI-APs and placebo or oral antipsychotics (oAPs) with regard to all-cause death (RR=0.64 and RR=0.71, respectively) and death due to suicide (RR=0.98 and RR=0.94, respectively).⁴
• Retrospective Cohort Studies: Several analyses assessed the risk of all-cause mortality of INVEGA SUSTENNA:
  • A real-world, retrospective study in Taiwan reported that over a mean follow-up of 1.04 years, the overall incidence of serious cardiovascular events, including severe ventricular arrhythmias (SVAs), cardiac arrest, and sudden death, was 3.92 (95% confidence interval [CI], 2.86-5.25) per 1000 patient-years.⁵
  • In a retrospective study using the EUDRAVigilance database, the fatality rate was not significantly different between INVEGA SUSTENNA and INVEGA TRINZA vs other SGA-LAIs (5.7% vs 5.6%, respectively; P=0.693).⁶
  • In a retrospective, observational study using the French pharmacovigilance database, the composite mortality rate for patients treated with either INVEGA SUSTENNA or INVEGA TRINZA was 0.06 per 1000 patients (95% CI, 0.03 per 100 to 0.09 per 1000), which was not significantly different from the rate for oral (0.09 per 1000 patients) or injectable risperidone (0.04 per 1000 patients).⁷
  • In a population-based study of patients with schizophrenia or schizoaffective disorder enrolled in the Taiwan National Health Insurance database who were prescribed an AP from 2015-2019, the risk of all-cause death was not increased in patients initiated with LAI paliperidone in comparison with oral paliperidone.⁸
    • aHR: 0.98 (95% CI, 0.68-1.40) INVEGA SUSTENNA vs oral paliperidone.
  • A cohort study of patients diagnosed with schizophrenia between 2002-2017 in Taiwan who transitioned to an LAI found 33% lower all-cause mortality (aHR=0.67; 95% CI, 0.52-0.78) vs propensity score matched patients on oAPs.⁹
    • INVEGA SUSTENNA resulted in a 70% reduction in all-cause mortality (aHR=0.30; 95% CI, 0.08-0.98; P=0.03) vs the equivalent oAP.          
  • In a Swedish cohort analysis, for monotherapy antipsychotic treatments, the lowest mortality was reported with INVEGA SUSTENNA (aHR: 0.11, 0.03-0.43) compared with no use, and a 51% reduction in mortality (aHR: 0.49, 0.2,1.18) when pairwise compared against oral paliperidone.¹⁰
  • Another study calculated mortality rate similar to the INVEGA SUSTENNA-associated rate observed in Japan’s postmarketing surveillance (10.7 vs 8.76 per 1,000 people per year, respectively.¹¹
• Japan Early Postmarketing Phase Vigilance (EPPV) Period: The estimated mortality reporting rate for INVEGA SUSTENNA in the 6-month Japanese early EPPV program was 5.84 per 1,000 patient-years, which was consistent with the mortality incidence rates from other clinical trials and observational patient cohorts in Japan. However, the mortality reporting rate in Japan was much higher than that observed passively in the United States (US) and globally after the launch of INVEGA SUSTENNA (0.43 and 0.38 per 1000 person-years, respectively). The observed mortality reporting rate in Japan may be attributed to a variety of factors, other than a risk with INVEGA SUSTENNA necessarily, including the effectiveness of mortality reporting in this unique EPPV program, advanced age, high CV risk factors, multiple underlying diseases and high antipsychotic polypharmacy use among cases with fatal outcomes.¹²

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 of paliperidone, respectively.

CLINICAL STUDIES

Meta-Analyses

Correll et al (2022)³ conducted a systematic review and meta-analysis to identify the most relevant specific causes of mortality and antipsychotic treatments, as well as analyze the factors aggravating or attenuating mortality in individuals with schizophrenia. The primary outcome was risk reduction of all-cause mortality in patients with schizophrenia versus any control group.

A total of 135 studies ranging from 1957 to 2021 were in the analysis, including 4,536,447 patients with schizophrenia compared with 1,115,600,059 patients in the general population.

• Schizophrenia was associated with significantly higher all-cause mortality as compared with any control group across 79 studies (RR=2.52; 95% CI, 2.38-2.68). In 57 studies, patients with schizophrenia had higher all-cause mortality versus the general population (RR=2.94; 95% CI, 2.75-3.13).
• Across 11 studies, reduction of all-cause mortality risk versus no antipsychotic treatment differed across antipsychotic treatment subgroups (RR=0.71; 95% CI, 0.59-0.84), with the largest effect by treatment in the following order:
  • Any SGA-LAIs (RR=0.39; 95% CI, 0.27-0.56; n=3 studies)
  • Clozapine (RR=0.43; 95% CI, 0.34-0.55; n=3 studies)
  • Any LAI (RR=0.47; 95% CI, 0.39-0.58; n=2 studies)
  • Any oral SGA (RR=0.47, 95% CI, 0.45-0.50; n=4 studies)
  • Any first-generation antipsychotic (FGA) LAI (RR=0.50; 95% CI, 0.43-0.57; n=3 studies)
  • Any SGA (RR=0.53; 95% CI, 0.44-0.63;n=4 studies)
  • Any oral antipsychotic (RR=0.64; 95% CI, 0.51-0.80; n=4 studies)
  • Any FGA (RR=0.73; 95% CI, 0.55-0.97; n=5 studies)
• In 1 incident (cases newly identified within the observation period or all new cases of schizophrenia) and 2 prevalent (all individuals living with schizophrenia within a specific timeframe) schizophrenia studies, the largest protective association emerged for SGA-LAIs (RR=0.15; 95% CI, 0.04-0.55 and RR=0.42; 95% CI, 0.29-0.59, respectively).
• Reduction of suicide-related mortality versus no antipsychotic treatment differed across antipsychotic groups with the largest effects for clozapine (RR=0.22; 95% CI, 0.16-0.30; n=2 studies) followed by any SGA-LAI (RR=0.43; 95% CI, 0.24-0.78; n=1 studies).
• Cardio-cerebrovascular-related mortality was higher in patients with schizophrenia vs both the general population and control matched groups (RR=2.03; 95% CI, 1.68-2.45; n=30 studies)
• Comorbid substance use disorder in patients with schizophrenia significantly increased all-cause mortality (RR=1.62; 95% CI, 1.47-1.80; n=3 studies)

Kishi et al (2016)⁴ conducted a series of meta-analyses to determine whether LAI-APs affect the mortality rate of patients with schizophrenia. The meta-analyses of randomized controlled trials (RCTs) compared all-cause death (primary) and death due to suicide in patients receiving LAI-APs (individual and pooled) vs placebo; LAI-APs (individual and pooled) vs oAPs; and head-to-head comparisons of LAI-APs. A total of 52 RCTs were included (N=17,416 [LAI-APs=11,360; oAPs=3,910; placebo=2,146]). Of the trials analyzed, paliperidone and risperidone were primarily studied (n=16 and n=18, respectively).

• LAI-APs vs Placebo: Median trial duration was 13 weeks. Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone and risperidone) differed from placebo with respect to incidences of all-cause death (pooled LAI-APs: risk ratios [RR]=0.64; P=0.37) or death due to suicide (pooled LAI-APs: RR=0.98; P=0.98). However, in a subanalysis utilizing only short-duration RCTs (≤13 weeks), pooled LAI-APs trended towards a lower incidence of all-cause death vs placebo (RR=0.29; 95% CI, 0.07-1.16; P=0.08).
• LAI-APs vs oAPs: Median trial duration was 52 weeks. Neither pooled nor individual LAIAPs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone and zuclopenthixol) differed from oAPs with respect to incidences of all-cause death (pooled LAI-APs: RR=0.71; P=0.30) or death due to suicide (pooled LAI-APs: RR=0.94; P=0.91).
• LAI-AP vs LAI-AP: Data for head-to-head LAI-AP comparisons was insufficient.

A limitation of analyzing mortality in RCTs is that patients with significant medical comorbidities, including substance use disorder, and who require significant co-medications are systematically excluded from these types of studies.  

Retrospective Cohort Studies

Shen et al (2024)⁵ conducted a real-world, retrospective, longitudinal cohort study using Taiwan’s National Health Insurance Research Database from March 2012 to December 2018 to evaluate the incidence rate and risk of cardiovascular events, including sudden death (defined as instantaneous death, death occurring in <24 hours from onset of symptoms, or death attributed to SVA), in patients with schizophrenia or schizoaffective disorder, who were treated with ≥1 SGA, following treatment with INVEGA SUSTENNA (primary cohort) vs oral SGAs (comparator cohort).

• The study included 11,023 patients with a mean (standard deviation [SD]) age of 43.2 (12.2) years; 50.5% were male.
• During a mean (SD) follow-up of 1.04 (1.22) years:
  • Serious cardiovascular events, including SVAs, cardiac arrest, and sudden death, were reported in 45 patients on INVEGA SUSTENNA, with an overall incidence rate of 3.92 (95% CI, 2.86-5.25) per 1000 patient-years.
  • Expanded serious cardiovascular events, including SVAs, cardiac arrest, sudden death, acute myocardial infarction, and ischemic stroke, were reported in 90 patients on INVEGA SUSTENNA with an overall incidence rate of 7.88 (95% CI, 6.33-9.68) per 1000 patient-years.
• In the comparative cardiovascular risk analysis, 92% (n=10,115) of the primary INVEGA SUSTENNA cohort was matched at 1:1 with the comparator oral SGA cohort.
• During the mean (SD) follow-up of 1.05 (1.24) and 0.74 (1.10) years for the primary and comparator cohorts, respectively:
  • Serious cardiovascular events were reported in 40 patients on INVEGA SUSTENNA vs 35 patients on oral SGAs (overall incidence rate: INVEGA SUSTENNA, 3.76 [95% CI, 2.68-5.12] per 1000 patient-years; oral SGAs, 4.70 [95% CI, 3.28-6.54] per 1000 patient-years).
  • Expanded serious cardiovascular events were reported in 81 patients on INVEGA SUSTENNA vs 69 patients on oral SGAs (overall incidence rate: INVEGA SUSTENNA, 7.64 [95% CI, 6.07-9.49] per 1000 patient-years; oral SGAs, 9.31 [95% CI, 7.24-11.78] per 1000 patient-years).
• The treatment groups had no significant differences in the risks of serious and expanded cardiovascular events.

Cicala et al (2023)⁶conducted a real-world, retrospective study analyzing Individual Case Safety Report (ICSR) data from the EUDRAVigilance database between 2011 and 2022 for the use of INVEGA SUSTENNA and INVEGA TRINZA.

• Of the 20,226 SGA-LAI-related ICSRs examined, 8,152 included INVEGA SUSTENNA- and/or INVEGA TRINZA-related reports.
• The fatality rate for INVEGA SUSTENNA and INVEGA TRINZA (n=8,152) vs other SGA-LAIs (n=12,170) was 5.7% (n=468) vs 5.6% (n=679; P=0.693).
• Among INVEGA SUSTENNA and INVEGA TRINZA users who had fatal outcomes, the number of co-reported additional drugs was significantly higher vs all INVEGA SUSTENNA and INVEGA TRINZA users (2.4 vs 1.6, respectively; P<0.001), however, there were no major differences in the type of co-reported medications.
• The most frequently reported fatal adverse drug reports (ADRs) were death (n=129; 21.8%), sudden death (n=47; 7.9%), completed suicide (n=98; 16.5%), pulmonary embolism (n=16; 2.7%), myocardial infarction (n=14; 2.4%), cardiac failure (n=13; 2.2%), and cardiorespiratory arrest (n=12; 2%).

Boels et al (2021)⁷ conducted a retrospective observational study to review paliperidone palmitate-related (PP-related) ADRs leading to death or life-threatening events from the French pharmacovigilance database between January 1, 2013 and December 31, 2019. PP-related death was defined as death of patient where the causality of PP is possible or probable; PP-related life-threatening event was defined as an event that required specific treatment in an intensive care unit that, if left untreated, would more likely than not result in death.

• Over the study period, 221,689 patients were estimated to have been treated with INVEGA SUSTENNA or INVEGA TRINZA.
• Of the 473 PP-related ADRs identified, 27 cases were included, of which there were 13 deaths and 14 life-threatening events.
• Most ADRs involved cardiorespiratory conditions or events (n=17, 63%), including sudden unexpected death (n=6), cardiac arrest due to torsades de pointes (n=2), cardiorespiratory arrest due to convulsive seizures (n=1), pulmonary embolism (n=6) and cardiomyopathy (n=2).
• In 23 cases (including 11 deaths), patients had been administered INVEGA SUSTENNA, while in the 4 remaining cases (including 2 deaths), patients were switching from INVEGA SUSTENNA to INVEGA TRINZA. Ten cases involved other suspected medications, mostly other antipsychotics.
• The median time from initiation to death or life-threatening event was 4 months.

Tang et al (2021)⁸ conducted a population-based, retrospective cohort study (January 1, 2015 – November 30, 2019) in patients with schizophrenia or schizoaffective disorder who had initiated treatment with LAI vs oAPs.

• A total of 29,779 patients were identified as new users of LAIs, of whom 10,747 initiated treatment with INVEGA SUSTENNA. Twenty-three completed suicides, and 84 all-cause deaths were reported.
• The unadjusted incidence rate of all-cause death during the active treatment period was 7.40 per 1,000 person-years (95% CI, 5.94-9.11), and the rate of completed suicide was 2.03 per 1,000 person-years (95% CI, 1.32-2.99).
• In a comparative analysis, the adjusted hazard ratio (aHR) for INVEGA SUSTENNA compared with oral paliperidone was 0.98 (95% CI, 0.68-1.40) for the risk of all-cause death and 0.67 (95% CI, 0.35-1.29) for the risk of completed suicide.

Huang et al (2021)⁹ conducted a population-based, retrospective cohort study in patients newly diagnosed with schizophrenia between January 1, 2002 and December 31, 2017 who were between the ages of 16 and 65 and received a prescription for an AP. Patients who were switched from an oral AP to an LAI and received at least 4 prescriptions in 1 year were compared against a propensity-matched cohort of patients who were not switched to an LAI.

• 2,462 patients who switched to an LAI met criteria for inclusion and only differed from the propensity-matched OAP cohort by being more likely to have had a suicide attempt and psychiatric ED visit in the 6 months prior to the index date and these covariates were adjusted for as part of the statistical analysis.
• All-cause mortality was 33% lower in the LAI group (aHR=0.67; 95% CI, 0.55-0.83)
  • Suicide mortality was lower in the LAI group but did not reach significance (aHR=0.77; 95% CI, 0.56-1.07)
  • Suicide attempts were 28% lower in the LAI group (incident rate ratio=0.72; 95% CI 0.54-0.95; P=0.02). The incident rate ratio was estimated using a negative binomial regression model adjusted for the Charlson Comorbidity Index score (within 1 yr prior to the index date), suicide attempts, and the number of psychiatric ED visits (within 6 months prior to the index date)
• In a subgroup analysis of patients who switched to an LAI within 2 years of diagnosis (n=702), all-cause mortality was not significant vs the OAP group (aHR=0.95; 95% CI, 0.67-1.34)
  • Suicide mortality was significantly lower (47% decreased risk) in the group switched to an LAI within 2 years of diagnosis (aHR=0.53; 95% CI, 0.30-0.92)
• INVEGA SUSTENNA resulted in a 70% reduction in all-cause mortality when compared against the equivalent OAP (aHR=0.30; 95% CI, 0.08-0.98; P=0.03)        

Taipale et al (2018)¹⁰ conducted a cohort analysis of all-cause mortality during antipsychotic treatment (July 1, 2006 – December 31, 2013) in Swedish schizophrenia patients, aged 16-64.

• LAI use was associated with a 33% lower risk of death compared with oral agents
  (aHR: 0.67, 0.56-0.80, P<0.0001).
• For monotherapy treatments, the lowest mortality was reported with INVEGA SUSTENNA use (aHR: 0.11, 0.03-0.43) compared with no use, and corresponding analysis of concomitant use with other antipsychotics showed similar results.
• Pairwise comparisons were performed to evaluate LAIs vs their oral equivalents and a 51% reduction in mortality was observed with INVEGA SUSTENNA (aHR: 0.49, 0.2-1.18) vs oral paliperidone.  

Suzuki et al (2017)¹¹ conducted a retrospective cohort study (June 2009 – December 2017) of patients with schizophrenia administered INVEGA SUSTENNA, risperidone LAI, or oral paliperidone (N=744). Of the 99 patients who received INVEGA SUSTENNA, 1 death (suicide) was reported, with a calculated mortality rate similar to the INVEGA SUSTENNA-associated rate observed in Japan’s postmarketing surveillance (10.7 vs 8.76 per 1,000 people per year, respectively).

EPPV - Japan

Pierce et al (2016)¹² analyzed the mortality events reported during the EPPV period in Japan following the approval of INVEGA SUSTENNA (November 19, 2013 - May 18, 2014). The EPPV, a unique pharmacovigilance system, was established in Japan in 2001 to promote the rational use of drugs in medical treatment and prompt actions for the prevention of serious ADRs. The EPPV requires the marketing authorization holder to collect adverse events (AEs) through intensive monitoring at least every 2 weeks for the initial 2 months and at least once monthly thereafter for the next 4 months following a product approval.

During the EPPV period it was estimated that 10,962 patients were treated with INVEGA SUSTENNA in Japan with an estimate exposure of 5,481 person-years. During that period, 32 deaths were reported leading to a higher all-cause mortality rate in Japan than that observed passively in the US or globally following the launch of INVEGA SUSTENNA (5.84, 0.43 and 0.38 per 1,000 patient-years, respectively). Categorization and reported causes of death are provided in the Table: Japan EPPV - Categorization and Causes of Death. At the time of death, 67.7% (21/31) of patients received a INVEGA SUSTENNA dose of 156 mg (n=11) or 234 mg (n=10). Autopsies were performed in 4 of the fatal cases. The individual causes of death were reported as asphyxia due to vomitus, neuroleptic malignant syndrome, and acute respiratory failure in 3 of the cases. Results from the 4^th case were not available.

The authors note that the observed rate does not necessarily result from a risk with INVEGA SUSTENNA treatment in Japanese patients and may be attributed to a variety of factors in these 32 patients:

• Advanced age (>50 years, n=19)
• High antipsychotic polypharmacy use among cases with fatal outcomes (n=25); Japan 78.1% vs Rest of World (ROW) 33.8%
  • 1 concomitant antipsychotic (n=10; 40%)
  • 2 concomitant antipsychotics (n=7; 28%)
  • ≥ 3 concomitant antipsychotics (n=8; 32%)
• High CV risk factors (n=23; >1 risk factor, n=14); Most frequently reported:
  • Smoking (39.1%)
  • Hypertension (26.1%)
  • Diabetes (21.7%)
  • Alcoholism (21.7%)
  • Obesity (17.4%)
• Multiple underlying diseases
  • Hypo/hypertension (n=7)
  • Diabetes (n=5)
  • CV disorder (n=4)
  • Dyslipidemia (n=3)
  • Pneumonia (n=3)
  • Asthma (n=3)
  • Malignancy (n=2)
  • Trisomy-21 (n=1)
• AE reporting rates for INVEGA SUSTENNA in Japan are 3.54 times higher than the ROW possibly due to the unique EPPV program vs passive reporting
• Four “Dear Doctor Letters” were distributed in Japan during the EPPV which may have triggered reporting of fatal cases (solicited vs spontaneous)

Phase 4 Study

A phase 4, open-label, 25-week study of 353 Chinese patients with schizophrenia on INVEGA SUSTENNA treatment reported a total of 8 deaths, including 4 completed suicides and 2 unexplained deaths. Two of the 4 patients with a completed suicide had documented prior suicide attempts, and recent hospital admissions were reported in 3 of the 4 patients with completed suicides.¹⁸

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 05 December 2024. Individual case reports and case series were excluded from this summary.