Summary

• The following information characterizes the adverse event (AE) profile of INVEGA TRINZA relative to INVEGA SUSTENNA (paliperidone palmitate 1-month).
• INVEGA TRINZA, a 3-month injection, is indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA for ≤4 months.¹
• Noninferiority between INVEGA TRINZA and INVEGA SUSTENNA was established in a long-term, double-blind (DB), randomized, controlled trial. The median time-to-relapse was not estimable in either group due to the low rate of relapse. Comparable safety and tolerability profiles for INVEGA SUSTENNA and INVEGA TRINZA were observed over the 48-week DB phase of the trial.²
• In a long-term maintenance trial, 506 patients with schizophrenia received several doses of INVEGA SUSTENNA during a 17-week, open-label (OL) phase and 379 patients continued into a 12-week, OL phase and received a single injection of INVEGA TRINZA. Subsequently, 160 patients were randomized to INVEGA TRINZA and 145 patients to placebo during the DB placebo-controlled phase.³
  • The most common (incidence at least 2% and greater than placebo) treatmentemergent adverse events (TEAEs) with INVEGA TRINZA in the DB phase were injection site reaction, weight increased, headache, nasopharyngitis, upper respiratory tract infection, akathisia, cough, and urinary tract infection.
  • The safety profile of INVEGA TRINZA was generally consistent to that seen with INVEGA SUSTENNA. No new safety signals were detected.
• In a retrospective analysis, 8,152 Individual Case Safety Reports (ICSRs) related to INVEGA TRINZA and/or INVEGA SUSTENNA reported on European Union Drug Regulating Authorities Vigilance (EUDRAVigilance) were analyzed and compared to a reference group of second generation-long-acting injectable antipsychotics (SGA-LAI).⁴
  • Serious adverse drug reactions (ADR) were reported in 5,264 (64.6%) INVEGA TRINZA and INVEGA SUSTENNA related ICSRs.
  • The most common ADRs reported were in the system organ class (SOC) of ‘psychiatric disorder’ and ‘general disorder and administration-site conditions’ for INVEGA TRINZA vs INVEGA SUSTENNA ICSRs (P<0.001).
  • Significantly higher rates of Standardized Medical Dictionary for Regulatory Activities (MedDRA^®) reports were observed for ‘sexual dysfunction’, ‘hemodynamic edema, effusions and fluid overload’ and ‘fertility disorders’ in the INVEGA TRINZA and INVEGA SUSTENNA group relative to the SGA-LAI group.  
  • Safety and tolerability findings for INVEGA TRINZA and INVEGA SUSTENNA were consistent with that of other SGA-LAIs.

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate can be expressed in mg eq of paliperidone (active moiety) or mg 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.
• 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.

CLINICAL STUDIES

Savitz et al (2015)² 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 diagnosed with schizophrenia according to Diagnostic and Statistical Manual, 4^th Edition (DSM-IV) and a Positive and Negative Syndrome Scale score (PANSS) 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, 1429 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 predefined 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, placebo injections were given monthly when active therapy was not administered.

Results

• Baseline and demographic characteristics were similar between the INVEGA TRINZA and INVEGA SUSTENNA groups during the DB phase.
• The rate of relapse was similar between INVEGA TRINZA (n=37, 8%) and INVEGA SUSTENNA (n=45, 9%).
• The estimated Kaplan-Meier difference between INVEGA TRINZA and INVEGA SUSTENNA was found to be 1.2% (95% confidence interval: -2.7%, 5.1%), demonstrating that INVEGA TRINZA was noninferior to INVEGA SUSTENNA based on the predefined criteria.

Safety

• From OL baseline to DB endpoint (week 65), the mean weight increased by 2.19 kg for INVEGA TRINZA and 3.07 kg for the INVEGA SUSTENNA group.
• During the DB phase, weight gain was the most common TEAE and the overall percentage of patients with TEAEs was similar in both the INVEGA TRINZA and INVEGA SUSTENNA groups.
• Injection site-related TEAEs were 6% vs 8% in the INVEGA SUSTENNA group compared with INVEGA TRINZA, respectively. Induration, redness, and swelling were mild in nature and observed to be ≤5% in both groups, as evaluated by the investigator.
• Diabetes-mellitus and hyperglycemia-related TEAEs were 2.6% vs 4.9% in the INVEGA TRINZA group compared with INVEGA SUSTENNA, respectively, and the incidence of prolactin-related TEAEs was similar in both groups.

Additional safety data are shown in Table: Summary of TEAEs (Intent-to-Treat [OL] Analysis Set and Safety Analysis Set) and in Table: Change in Serum PRLs.

Retrospective Study

Cicala et al (2023)⁴ conducted a retrospective analysis of the ADRs related to INVEGA TRINZA and INVEGA SUSTENNA and compared them with those occurring with other SGA-LAIs.

Study Design/Methods

• ICSRs suspected to be associated with INVEGA TRINZA and/or INVEGA SUSTENNA were retrieved from the EUDRAVigilance database between January 2011 and June 2022.
• ICSRs showing at least 1 SGA-LAIs (eg, olanzapine, aripiprazole, and risperidone) were retrieved from EUDRAVigilance between January 2003 and June 2021 to establish the reference group.
• Descriptive analyses were performed on demographic and AE characteristics. All the ADRs were classified according to MedDRA^® hierarchy.

Results

• Overall, 20,226 ICSRs related to SGA-LAIs were retrieved from EUDRAVigilance during the observation period, of which, 8,152 ICSRs were related to INVEGA TRINZA and/or INVEGA SUSTENNA (INVEGA TRINZA, n=1,731; INVEGA SUSTENNA, n=6,332; INVEGA TRINZA and INVEGA SUSTENNA, n=89).
• The mean dose and median duration of treatment, respectively, were 599 mg and 244 days for INVEGA TRINZA and were 189 mg and 120 days for INVEGA SUSTENNA.

Safety

• Overall, in the INVEGA TRINZA and/or INVEGA SUSTENNA group, ≥1 serious ADR was reported in 5,264 (64.6%) ICSRs.
• Most frequent ADRs (≥5%) reported in the INVEGA TRINZA and INVEGA SUSTENNA groups based on SOC are described in Table: Summary of Most Frequent ADRs Observed in INVEGA TRINZA and INVEGA SUSTENNA ICSRs.

• Specific ADRs in INVEGA TRINZA ICSRs by SOC were⁵:
  • Psychiatric disorders: schizophrenia (n=174), psychotic disorder (n=97), psychotic symptoms (n=69), delusion (n=54), psychotic decompensation (n=53), and anxiety (n=47).
  • Nervous system disorders: extrapyramidal disorder (n=33), tremor (n=28), somnolence (n=25), sedation (n=23), headache (n=22),and akathisia (n=19).
  • General disorder and administration-site conditions: drug ineffectiveness (n=158), condition aggravated (n=101), malaise (n=49), fatigue (n=48), injection-site pain (n=36) and injection-site induration (n=32).
• Significantly higher rates of Standardized MedDRA reports were observed for ‘sexual dysfunction’ (Reporting odds ratio [ROR], 1.45), ‘hemodynamic edema, effusions and fluid overload’ (ROR, 1.42) and ‘fertility disorders’ (ROR, 2.69) in the INVEGA TRINZA and INVEGA SUSTENNA group relative to the SGA-LAI group.  
• Safety and tolerability findings for INVEGA TRINZA and INVEGA SUSTENNA were consistent with that of other SGA-LAIs.

Limitations

• The granularity of data provided by EUDRAVigilance is limited; therefore, a conservative approach was followed in cases of incomplete information which led to frequent case exclusion and downgrading of reported items.
• Cases reported by clinicians were analyzed retrospectively, without a homogenous structure of single research protocol. Therefore, by applying the cluster analysis method, this made the secondary analysis of these data speculative.
• The pharmacovigilance data may have technical concerns, including under-reporting of ADRs compared to global clinical population and difficulty in identifying confounders, making them potentially under-representative.
• The incidence of ADRs could not be calculated due to the lack of data related to the number of patients treated effectively with long-acting injections in the considered time.

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 16 May 2024.