Summary

• Injection-site reaction was among the most common adverse reactions (≥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) in the long-term maintenance study.¹
• According to subject ratings of injection-site pain in the single-dose phase 1 study, deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale.²
• Redness and swelling were observed in ≤2% of subjects in the INVEGA TRINZA and placebo groups during the DB phase of the long-term maintenance study, and were rated mild by investigators.³
• In a DB, active-controlled, noninferiority study, injection-site pain was reported in ≥2% of patients receiving INVEGA SUSTENNA/INVEGA TRINZA in the OL phase and those receiving INVEGA TRINZA or INVEGA HAFYERA during the DB phases.⁴
• In a DB noninferiority study, investigator-rated induration, redness and swelling, which were primarily mild in nature, were observed in ≤5% of patients in the INVEGA SUSTENNA and INVEGA TRINZA groups and were similar between groups over time.^5,6
• INVEGA TRINZA is intended for intramuscular use only. Inject slowly, deep into the deltoid or gluteal muscle. Alternate injections between the two deltoid muscles or the two gluteal muscles.⁷
• Published literature provides varied information on the maximum injection volume that is recommended for deltoid muscle administration (generally 0.1 mL - 2 mL).^8-18 Because the deltoid is a small and sometimes poorly developed muscle, injections should be given in the densest part of the muscle. Furthermore, since the deltoid injection-site is relatively small and is proximal to the axillary and radial nerves, the precise location of the injection-site is important and the volume that should be used to ensure safe delivery is limited.^{8,12-14,19-24}
• A search of the current literature did not identify any data discussing the use of topical anesthetics, ice/cooling techniques, warm compresses or muscle massage for the prevention or treatment of injection-site reactions specific to INVEGA TRINZA. It is unknown how such techniques might affect the unique properties of INVEGA TRINZA, and therefore, cannot be recommended.

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 mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States (US). 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.
• 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.

CLINICAL STUDIES

Pivotal Study

Berwaerts et al (2015)^3,25 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 at least 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 OL transition phase, all patients except those who were receiving other long-acting injectable 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 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 OL 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, including injection-site evaluations.

Results

• Across the entire OL phase, all treatment-emergent injection-site adverse events were mild or moderate in intensity, non-serious, and did not result in discontinuation.²⁵ In the US, patients most often chose the deltoid muscle as their injection-site.²⁶
• During the DB phase, 6 patients (4%) in the group receiving INVEGA TRINZA reported injection-site treatment-emergent adverse events (TEAEs), of which injection-site pain was most frequently reported (2 patients [1%]).²⁵ No patients in the group receiving PBO reported treatment-emergent injection-site adverse events during the DB phase.²⁵ In the US, patients most often chose the deltoid muscle as their injection-site.²⁶
  • Based on investigator ratings of the injection-site, redness and swelling were observed in ≤2% of patients in the INVEGA TRINZA and PBO groups and were rated as mild. There were no reports of induration in either group during this time.³
• Patient evaluations of injection pain during the DB phase were similar for the PBO and INVEGA TRINZA groups (mean baseline: PBO: 12.9, INVEGA TRINZA: 15.8; mean endpoint: PBO: 13.0, INVEGA TRINZA: 15.1) based on a 100-mm visual analog scale (VAS).²⁵ Injection-site pain scores are also presented based on injection-site location in figure: Subject-Rated Pain Scores Based on Injection Site.²⁶

The long-term maintenance study was not specifically designed to evaluate the dose response of INVEGA TRINZA for safety or tolerability. However, subjects' evaluations of the pain intensity of the current injection by DB dose level in subjects assigned to INVEGA TRINZA did not show any dose-dependent trend. At DB end point, the subjective ratings had decreased in the 273/410 mg and the 819 mg dose level subgroups (from 16.3 to 13.6 and from 16.7 to 14.6, respectively), and increased in the 546 mg subgroup (from 14.9 to 15.9). In addition, there was no evidence of a dose effect with regards to the investigators' evaluations of injection site over time. Across dose level subgroups, all of the parameters evaluated (induration, pain, redness, and swelling) were rated as absent in 98-100% of the cases, and the remainder of the cases were rated as mild.³ Furthermore, 86-88% of patients received fixed doses of INVEGA TRINZA that were in the higher end of the dosing range of 546 mg (1.75 mL) or 819 mg (2.625 mL).²⁶ Additional VAS pain scores based on volume of injection are presented in Figure: Subject-Rated Pain Scores Based on Volume of Injection (INVEGA TRINZA – DB Phase).²⁶

In a phase 1 study, patients with schizophrenia received a single injection of INVEGA TRINZA concomitantly with other oral antipsychotics. Patient ratings of injection-site pain allowed for assessment of the temporal course of injection-site pain. Residual injection pain peaked for 1 or 6 hours after injection and trended downward 3 days after the injection. Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale.^2,3 This study, which preceded the phase 3, long-term maintenance study, included patients that were randomized to the highest volume dosing group (2.6 mL) for both gluteal and deltoid injections.²

Noninferiority Studies

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

Study Design/Methods

• The study consisted of 3 phases as follows: a 28-day screening phase, a 1- to 3-month OL maintenance phase (depending on the treatment received, INVEGA SUSTENNA or INVEGA TRINZA), and a 12-month 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 a Positive and Negative Syndrome Scale (PANSS) total score of <70 points at the time of screening.
• All 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 those who received INVEGA TRINZA 546 or 819 mg in the OL phase continued at the same dose during the DB phase.
  • Patients who received moderate doses of INVEGA SUSTENNA 156 mg or INVEGA TRINZA 546 mg during the OL phase were assigned to receive a moderate dose of INVEGA HAFYERA 1,092 mg in the DB phase, and those who received high doses of INVEGA SUSTENNA 234 mg or INVEGA TRINZA 819 mg during the OL phase were assigned to receive a high dose of INVEGA HAFYERA 1,560 mg during the DB phase.

Results

• Overall, 838 patients were enrolled in the study, and 702 (83.8%) patients who completed the OL phase were further randomized to the DB phase (INVEGA HAFYERA: 478; INVEGA TRINZA: 224).
  • During DB phase, in INVEGA HAFYERA vs INVEGA TRINZA group the mean duration of exposure was 329.8 days vs 336.4 days; and mean dose was 1,334.73 mg vs 689.82 mg.
• Injection-site pain was the most common (≥2% of patients) TEAE reported during OL and DB phases. See Table: Summary of InjectionSite-Related TEAEs in the OL and DB Phases.

Savitz et al (2016)⁵ 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. A separate analysis of safety data from the noninferiority study was conducted to evaluate the frequency of injection-site reaction and pain following administration of INVEGA SUSTENNA and INVEGA TRINZA.⁶

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.⁵
• The study included patients between the ages of 18-70 years with a 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.⁵
• During the open label phase, 1429 patients received INVEGA SUSTENNA in the following doses⁵:
  • 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 the week 9 dose.
• 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 placebo injections given monthly when active therapy was not administered.⁵
• Assessments of injection-site reaction and pain were completed within 30 minutes after each injection. A VAS ranging from a score of 0 (no pain) to 100 (maximum pain) was used by patients to self-assess their injection pain intensity, while a 4-point scale (0=absent; 1=mild; 2=moderate; 3-severe) was used by blinded investigators to evaluate injection-site reaction for induration, redness, and swelling.⁶

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.⁵
• Injection-site data were collected for 1279 patients in the OL phase and 1015 patients in the DB phase. The majority of patients received their injections in the deltoid muscle (OL [INVEGA SUSTENNA]: 59%; DB [INVEGA TRINZA]: 55%; DB [INVEGA SUSTENNA]: 57%). The remaining received injections either in only gluteal muscle or both gluteal and deltoid muscle.⁶
• Mean VAS scores decreased from 22 at OL baseline to 19.2 at DB endpoint. A decrease in mean VAS scores was observed in both treatment groups from DB baseline (INVEGA TRINZA [19.5], INVEGA SUSTENNA [18.4]) to DB endpoint (INVEGA TRINZA [15.6], INVEGA SUSTENNA [15.5]). Injection-site location (deltoid vs. gluteal), final OL dose of INVEGA SUSTENNA, and baseline BMI did not contribute to any notable changes in injection pain between the two treatment groups.⁶ Overall, injection site-related TEAEs were spontaneously reported in13% of patients in the OL phase, and in 6% of INVEGA SUSTENNA vs 8% of INVEGA TRINZA patients in the DB phase. The most common injection site-related TEAEs reported during the DB phase (>2% either treatment group) in the INVEGA TRINZA (N=504) vs INVEGA SUSTENNA (N=512) groups, respectively, were: pain (3% vs 2%) and induration (1% vs 3%).⁶
• Investigator-reported injection-site induration, redness and swelling were mild in nature and observed in ≤6% of subjects in the OL phase, and in ≤5% of subjects in both treatment groups in the DB phase. See Table: Investigator-Reported and -Rated Injection-Site Reactions. Discontinuations due to injection-site pain occurred in 2 patients (0.1%) in the OL phase and no patient in the DB phase.⁶

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 12 April 2024.