Summary

• The most common adverse reactions (incidence ≥5% in the open-label [OL] phase, or in the INVEGA TRINZA group and at least twice the incidence in the placebo (PBO) group during the double-blind [DB] phase) during the long-term maintenance trial in patients with schizophrenia included akathisia and parkinsonism.¹
• Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. The risk of developing TD and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase, but the syndrome can develop after relatively brief treatment periods at low doses, although this is uncommon. Therefore, the smallest dose and shortest duration of treatment producing satisfactory clinical response should be sought in patients requiring chronic antipsychotic administration. The need for continued treatment should be reassessed periodically. If signs and symptoms of TD appear in a patient treated with INVEGA TRINZA, drug discontinuation should be considered. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.¹
• In the DB, PBO-controlled, relapse-prevention study that evaluated the efficacy and safety of INVEGA TRINZA in delaying the time-to-relapse of schizophrenia symptoms, extrapyramidal symptoms (EPS)-related treatment-emergent adverse events (TEAEs; 8% vs 3%; [akathisia, 4% vs 1%]) were among the most common TEAEs occurring more frequently in the INVEGA TRINZA vs PBO group.²
• In a randomized, parallel-group, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA, EPS-related TEAEs were similar between groups during the DB phase (8% and 7%, respectively). Akathisia was the most common TEAE reported in the INVEGA TRINZA and INVEGA SUSTENNA groups during the DB phase (4% and 3%, respectively).³
• In a phase 3, randomized, DB, multicenter, noninferiority trial that evaluated the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA in adults with schizophrenia, during the DB phase, 8.5% and 9.6% of patients in the INVEGA TRINZA and INVEGA HAFYERA groups, respectively, experienced ≥1 EPS-related TEAE.⁴
• In an exploratory post hoc subgroup analysis of the OL phase 3b REMISSIO study that evaluated the efficacy and safety outcomes of INVEGA TRINZA according to patient age and disease duration, the TEAE of akathisia was reported in 4.9% vs 2.8% of patients in the younger vs older group and in 7.0% vs 2.6% of patients with ≤3 years vs >3 years of disease duration.⁵
• In a subgroup analysis of the OL REMISSIO study that evaluated the efficacy and safety of INVEGA TRINZA in the Asian patient population, TEAEs reported in the Asian patient subgroup vs overall population were akathisia (7.1% vs 3.6%) and extrapyramidal disorder (5.7% vs 1.3%).⁶

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate can be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to milligrams of paliperidone palmitate to reflect the commercially available INVEGA SUSTENNA and INVEGA TRINZA dosage strengths. The conversion factor from milligram equivalent to milligrams 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.
• INVEGA TRINZA doses expressed as 273, 410, 546, and 819 mg of paliperidone palmitate are equal to 175, 263, 350, and 525 mg eq of paliperidone, respectively.
• INVEGA HAFYERA doses expressed as 1,092 and 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq of paliperidone, respectively.

PRODUCT LABELING

Please refer to the following sections of the Full Prescribing Information¹ which are relevant to your inquiry: WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

SCHIZOPHRENIA CLINICAL STUDIES

Pivotal Trial

Berwaerts et al (2015)² conducted a DB, PBO-controlled, relapse-prevention study to evaluate the efficacy and safety of INVEGA TRINZA in delaying time-to-relapse of schizophrenia symptoms in patients previously treated with INVEGA SUSTENNA for ≥4 months.

Study Design/Methods

The study included 4 phases: a screening and oral tolerability testing phase of up to 3 weeks, a 17-week OL transition phase, a 12-week OL maintenance phase, and a DB phase of variable length. During the transition phase, all patients except those who were receiving other long-acting injectable (LAI) antipsychotics or those who were receiving INVEGA SUSTENNA before entering the study received 4 months of INVEGA SUSTENNA treatment. Dosing included the following: day 1: INVEGA SUSTENNA 234 mg (deltoid intramuscular [IM] administration); day 8: INVEGA SUSTENNA 156 mg (deltoid IM administration); days 36 and 64: INVEGA SUSTENNA 78, 117, 156, or 234 mg flexible doses (deltoid IM or gluteal IM administration); and day 92: the same dose of INVEGA SUSTENNA as was administered on day 64. During the maintenance phase, patients received a single dose of INVEGA TRINZA (273, 410, 546, or 819 mg; a 3.5-fold multiple of the final INVEGA SUSTENNA dose administered on day 92) in either the deltoid or gluteal muscle. During the DB phase, stabilized patients were randomized 1:1 to receive a fixed dose of INVEGA TRINZA (the same dose as during the maintenance phase) or PBO. In addition to efficacy, safety and laboratory parameters were measured.

Results

During the OL maintenance phase, 12 patients (3%) experienced EPS-related TEAEs. These included: restlessness (n=4; 1%), akathisia and musculoskeletal stiffness (n=2; 1% each), and drooling, muscle rigidity, parkinsonism, dyskinesia, dystonia, and tremor (n=1; 0.3% each). During the DB phase, EPS-related TEAEs (8% vs 3%; [akathisia, 4% vs 1%]) were among the most common TEAEs occurring more frequently in the INVEGA TRINZA group than in the PBO group. See Table: EPS Assessed by Rating Scale Incidence in the DB Phase. During the DB phase, anticholinergic medication was used by 11% of the INVEGA TRINZA group and by 9% of the PBO group.

Noninferiority Trials

Savitz et al (2016)³ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA. The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase.

Study Design/Methods

The study consisted of 4 phases: a 3-week screening phase, a 17-week, OL stabilization phase, a 48-week DB phase, and a follow-up phase.

The study included patients between the ages of 18-70 years with a Positive and Negative Syndrome Scale (PANSS) score between 70-120 who had worsening schizophrenia symptoms and discontinued other antipsychotics due to insufficient efficacy, safety or tolerability issues with current treatment, or those with a preference for injectable medications.

During the OL phase, 1,429 patients received INVEGA SUSTENNA in the following doses:

• Day 1: 234 mg (deltoid administration)
• Day 8: 156 mg (deltoid administration)
• Weeks 5 and 9: flexible dosing between 78-234 mg (deltoid or gluteal administration). The week 13 dose was the same as week 9

Based on pre-defined criteria, patients who were clinically stable after completing the OL phase were randomized (1:1) into the DB phase. Patients in the DB phase received fixed doses of INVEGA SUSTENNA (78, 117, 156 or 234 mg; n=512) or INVEGA TRINZA (273, 410, 546, 819 mg; n=504) in the deltoid or gluteal muscle. In the INVEGA SUSTENNA group, injections occurred every 4 weeks, and in the INVEGA TRINZA group, active drug was administered every 3 months along with PBO injections given monthly when active therapy was not administered.

Results

The mean duration of exposure was 295.1 days for INVEGA TRINZA at a mean dose of 647.01 mg and 286.7 days for INVEGA SUSTENNA at a mean dose of 185.8 mg. During the OL phase, 13% of patients experienced EPS-related TEAEs. The incidence of EPS-related TEAEs was similar between the INVEGA TRINZA and INVEGA SUSTENNA groups during the DB phase (8% and 7%, respectively). Akathisia was the most common TEAE reported in 6% of the patients in the OL phase, and 4% and 3% of patients in the INVEGA TRINZA and INVEGA SUSTENNA group, respectively, during the DB phase. Results for the EPS scales are found in Table: Changes in EPS Scales from DB Baseline to Endpoint, Safety Analysis Set. TD was reported in 3 patients (INVEGA SUSTENNA [OL phase]; INVEGA SUSTENNA [OL/DB phases]; INVEGA TRINZA [DB phase]). More patients in the INVEGA TRINZA vs INVEGA SUSTENNA group received anti-EPS treatment during the DB phase (16% vs 13%, respectively).

Noninferiority of Paliperidone Palmitate 6-Month vs INVEGA TRINZA

Najarian et al (2022)⁴ conducted a phase 3, randomized, DB, active-controlled, parallelgroup, multicenter, non-inferiority trial to evaluate the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA on time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA.

Study Design/Methods

The study consisted of 3 phases: a 28-day screening phase, a 1- to 3-month OL maintenance phase (depending on treatment received, INVEGA SUSTENNA or INVEGA TRINZA), and a 12month DB phase.

The study included patients aged 18-70 years with a Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of schizophrenia for ≥6 months before screening, and PANSS total score of <70 points at the time of screening.

Patients received 1 dose of either INVEGA SUSTENNA or INVEGA TRINZA in the OL maintenance phase. During the DB phase, patients were randomized (2:1) to receive equivalent doses of INVEGA HAFYERA or INVEGA TRINZA.

• Patients who received INVEGA SUSTENNA 156 or 234 mg in the OL phase were assigned to receive INVEGA TRINZA 546 or 819 mg during the DB phase, and patients who received INVEGA TRINZA 546 or 819 mg in the OL phase continued at same doses during the DB phase.
• Patients who received INVEGA SUSTENNA 156 mg or INVEGA TRINZA 546 mg during the OL phase were assigned to receive INVEGA HAFYERA 1,092 mg in the DB phase, and those who received INVEGA SUSTENNA 234 mg or INVEGA TRINZA 819 mg during the OL phase were assigned to receive INVEGA HAFYERA 1,560 mg during the DB phase.

Results

Overall, 838 patients were enrolled in the study and 702 patients who completed the OL phase were further randomized to the DB phase (INVEGA HAFYERA=478, INVEGA TRINZA=224). During the OL phase 6.3% patients experienced ≥1 EPS-related TEAEs. In the DB phase, 8.5% of patients in the INVEGA TRINZA group and 9.6% of patients in the INVEGA HAFYERA group experienced ≥1 EPS-related TEAEs. Most common EPS-related TEAEs (>5 patients) in the INVEGA TRINZA vs INVEGA HAFYERA groups were parkinsonian rest tremor (0.9% vs 1.9%), muscle rigidity (0% vs 0.4%), parkinsonism (0.9% vs 1.3%), akathisia (3.6% vs 3.6%), dyskinesia (0.9% vs 1.3%), dystonia (0% vs 0.2%), and tremor (0% vs 0.2%).

Giron-Hernandez et al (2023)⁷ conducted a post hoc subgroup analysis to evaluate the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA in adults with schizophrenia from European sites who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA.

Results

At European sites, 439 patients were enrolled or dosed in the OL phase and 384 patients were further randomized to the DB phase (INVEGA HAFYERA=260, INVEGA TRINZA=124). The EPS-related TEAEs in the INVEGA TRINZA vs INVEGA HAFYERA groups were parkinsonism (2.4% vs 4.6%), akathisia (2.4% vs 3.1%), dyskinesia (0% vs 1.9%), dystonia (0.8% each), and tremor (0.4% vs 0%).

REMISSIO Study

Pungor et al (2020)⁵ conducted an exploratory post hoc subgroup analysis of the singlearm, OL, 52-week, phase 3b REMISSIO study that evaluated the efficacy and safety outcomes of INVEGA TRINZA according to patient age (younger [<35 years] vs older [≥35 years]) and duration of disease (≤3 years vs >3 years).

Study Design/Methods

The study included adult patients with schizophrenia who were treated with INVEGA SUSTENNA for ≥4 months (the last 2 doses being the same) and then were transitioned to INVEGA TRINZA and had a PANSS total score of <70 at baseline.

Results

A total of 305 patients were included in the subgroup analysis (based on age: younger group, n=123; older group, n=182; based on disease duration: ≤3 years, n=72; >3 years, n=233). Of the TEAEs reported in ≥5% of patients in either group, akathisia was reported in 4.9% vs 2.8% of patients in the younger vs older group and in 7.0% vs 2.6% of patients with ≤3 years vs >3 years of disease duration. The change in mean (95% CI) extrapyramidal symptom rating scale (ESRS) scores from baseline to the last observation carried forward (LOCF) endpoint was similar in both age groups and in both disease duration groups.

Chung et al (2022)⁶ conducted a subgroup analysis of the OL, 52-week, phase 3b REMISSIO study to evaluate the efficacy and safety of INVEGA TRINZA in an Asian patient population with clinically stable schizophrenia in a naturalistic setting.

Study Design/Methods

Eligibility criteria as mentioned in Pungor et al.⁵ Eligible patients received 4 injections of INVEGA TRINZA during the 12-month treatment phase, that is, at day 1, 3 months, 6 months, and 9 months.

Results

Of the 305 patients enrolled in the study, 71 (23.3%) Asian patients were included in this subgroup analysis. TEAEs reported in the Asian subgroup vs overall population were akathisia (7.1% vs 3.6%) and extrapyramidal disorder (5.7% vs 1.3%).

Observational Study

Fernández-Miranda et al (2023)⁸ conducted an observational, 52-week prospective study to evaluate the dose-plasmatic levels-response relationship of monthly aripiprazole and INVEGA TRINZA in patients with severe schizophrenia who had been stabilized with INVEGA TRINZA or aripiprazole for ≥1 year.

Study Design/Methods

Overall, 68 patients were included in the study within 2 groups: standard doses (INVEGA TRINZA ≤819 mg/3 months or aripiprazole ≤400 mg/month) and higher doses. Of all patients, 22 patients were on standard doses of INVEGA TRINZA, 21 patients were on higher doses of INVEGA TRINZA, 12 patients were on standard doses of aripiprazole, and 13 patients were on higher doses of aripiprazole.

Results

A dose-dependent effect on parkinsonism was observed with INVEGA TRINZA, with greater occurrence at higher doses. At baseline, 22.8% of all patients reported parkinsonism, of which 91.2% of patients were on INVEGA TRINZA. At the end-of-study follow-up, 19.1% of all patients reported parkinsonism (P<0.05). At baseline vs at follow-up, 4.4% vs 4.2% of all patients reported akathisia.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug Files (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 October 2024.