Summary

• Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.¹ Clinical monitoring of weight is recommended.²
• In a long-term relapse prevention trial, 1% of patients in the placebo (PBO) group and 10% of patients in the INVEGA TRINZA group experienced a clinically significant increase in body weight (≥7%) from double-blind (DB) baseline to endpoint.³
• In a DB noninferiority study, a similar percentage of patients in both arms (INVEGA TRINZA: 15%; INVEGA SUSTENNA: 16%) experienced a ≥7% increase in weight from DB baseline to endpoint.⁴
• In a phase 3, DB, noninferiority study of INVEGA TRINZA and INVEGA HAFYERA, treatment-emergent adverse event (TEAE) of increased weight was reported in 17 (7.6%) vs 40 (8.4%) patients, and TEAE of decreased weight was reported in 7 (3.1%) vs 8 (1.7%) patients.⁵
  • In a post hoc subgroup analysis of patients enrolled in European investigational sites, weight increase was reported in 10 (8.1%) patients in the INVEGA TRINZA group and 13 (5.0%) patients in the INVEGA HAFYERA group during the DB phase.⁶
  • In another post hoc subgroup analysis of the Asian population, weight increase was reported in zero patients in the INVEGA TRINZA group and 2 (3.2%) patients in the INVEGA HAFYERA group during the DB phase.⁷
• In a prospective observational study, overall 4.6% of patient reported weight gain, and  4% of patients reported a >7% increase in weight.⁸
• A long-term follow-up analysis of a retrospective, observational study evaluating INVEGA TRINZA monotherapy in patients with schizophrenia reported that 4 out of 97 patients discontinued due to weight gain.⁹

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.
• INVEGA HAFYERA doses expressed as 1,092 or 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq. of paliperidone, respectively.

BACKGROUND

The use of second-generation antipsychotics (SGAs) has been associated with weight gain and metabolic abnormalities, which places patients at increased cardiovascular risk.¹⁰ Changes in body composition and weight gain may be contributing factors to the metabolic abnormalities observed in these patients. Because there are limited data in drug-naïve patients, it is unclear whether weight gain is due to the drug treatment or to the psychiatric disease itself. The prevalence of obesity in patients with schizophrenia has been estimated to be approximately 1.5- to 2-fold higher than the prevalence in the general population; however, lifestyle characteristics such as sedentary behavior may contribute to the higher prevalence of weight gain.^2,10 The mechanism of SGA-associated weight gain is unknown; however, altered binding affinities for serotonin, norepinephrine, dopamine, and histamine-H1 receptors may be implicated through alterations in appetite and satiety.¹⁰ Rapid weight gain may be observed over the first 2 to 3 months of treatment with an SGA (approximately 0.5 to 5.0 kg over 10 weeks); however, weight gain may extend past a year of treatment.¹⁰ The risk of weight gain with each antipsychotic medication should be a factor in treatment selection for patients with body mass index (BMI) values of ≥25.² Weight and BMI measurements should be checked routinely (at every visit or approximately every 4 weeks), especially for the first 3 to 6 months after treatment initiation or change in therapy and every 3 months thereafter.^2,10 For patients with BMI values ≥18.5, 1-unit increases in BMI indicate a need for intervention (closer monitoring of weight, participation in weight management program, use of weight loss therapies, or change in antipsychotic regimen).²

CLINICAL STUDIES

Berwaerts et al (2015)³ conducted a 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, open-label (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, increased weight (5%) was among the most frequently reported (≥2%) TEAE.
• During the DB phase, increased weight (9% vs 3%) was among the most common TEAE occurring more frequently in the INVEGA TRINZA group than in the PBO group. Decreased weight (8% vs 1%) was more frequent in the PBO group than in the INVEGA TRINZA group.
• The mean body weight increase from OL baseline to DB endpoint was 2.38 kg in the INVEGA TRINZA group and 0.55 kg in the PBO group. One of 145 (1%) patients in the PBO group and 15 of 160 (10%) patients in the INVEGA TRINZA group experienced a clinically significant increase in body weight (≥7%) from DB baseline to endpoint.

Savitz et al (2016)⁴ 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 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, active drug was administered every 3 months along with placebo 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 maintenance phase, increased weight (5%) was among the most frequently reported (≥2%) TEAE. The same percentage of patients (21%) in each arm reported increased weight during the DB phase. A decrease in weight was reported by 3% of patients in each arm.
• From OL baseline to DB endpoint, the mean increase in body weight was 2.19 kg and 3.07 kg in the INVEGA TRINZA (n=495) and INVEGA SUSTENNA (n=495) groups, respectively. In the INVEGA TRINZA group, 136 (27%) patients had a ≥7% increase in body weight as compared to 150 (30%) patients in the INVEGA SUSTENNA group.
• From DB baseline to endpoint, a similar percentage of patients in both arms (INVEGA TRINZA: 15%, n=75; INVEGA SUSTENNA: 16%, n=81) experienced a ≥7% increase in weight. Overall, 37 (7%) of INVEGA TRINZA-treated patients and 21 (4%) of INVEGA SUSTENNA-treated patients had a ≥7% decrease in body weight.

Najarian et al (2022)⁵ conducted a phase 3, randomized, DB, active-controlled, parallel-group, multicenter, noninferiority study to evaluate the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA on the time to the 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.

• Patients aged 18-70 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) diagnosis of schizophrenia for ≥6 months before screening and a PANSS total score of <70 points at the time of screening were included in the study.
• All patients received 1 dose of either INVEGA SUSTENNA or INVEGA TRINZA during 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 during the OL phase were assigned to receive INVEGA TRINZA 546 or 819 mg during the DB phase, respectively, and those who received INVEGA TRINZA 546 or 819 mg during 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 during 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 TRINZA, 224; INVEGA HAFYERA, 478).
  • During the DB phase, in the INVEGA TRINZA vs INVEGA HAFYERA group, the mean duration of exposure was 336.4 vs 329.8 days, and the mean dose was 689.8 vs 1,334.7 mg.
• During the OL phase, TEAE of increased and decreased weight were reported in 8 (1.0%) and 4 (0.5%) patients, respectively, in the INVEGA SUSTENNA/INVEGA TRINZA group.
• During the DB phase, in the INVEGA TRINZA vs INVEGA HAFYERA group, TEAE of increased weight was reported in 17 (7.6%) vs 40 (8.4%) patients, and TEAE of decreased weight was reported in 7 (3.1%) vs 8 (1.7%) patients.

Post Hoc Subgroup Analyses of the DB Phase of the Noninferiority Study

Giron-Hernandez et al (2023)⁶ reported the results of a post hoc subgroup analysis of the noninferiority study that evaluated 384 patients with schizophrenia who were enrolled in European investigational sites and received INVEGA TRINZA (n=124) or INVEGA HAFYERA (n=260). In the DB phase, weight increase was reported in 10 (8.1%) patients in the INVEGA TRINZA group and 13 (5.0%) patients in the INVEGA HAFYERA group.

Richarz et al (2023)⁷ reported the results of a post hoc analysis of the Asian subgroup enrolled in the noninferiority study. Ninety patients were evaluated in this subgroup (INVEGA TRINZA, n=28; INVEGA HAFYERA, n=62). In the DB phase, weight increase was reported in zero patients in the INVEGA TRINZA group and 2 (3.2%) patients in the INVEGA HAFYERA group. Overall, a mean weight increase of 1.36% was reported in the INVEGA TRINZA group, and a mean weight decrease of -0.62% was reported in the INVEGA HAFYERA group.

Mauri et al (2022)⁸ conducted a prospective observational study to evaluate the maintenance of clinical efficacy and tolerability, and variation in paliperidone palmitate plasma levels during the transition from INVEGA SUSTENNA to INVEGA TRINZA.

Study Design/Methods

• Patients aged 18-66 years with schizophrenia were included, and the observation was ongoing at the time of reporting.
• All patients were stabilized on INVEGA SUSTENNA for 4 months, after which they were switched to INVEGA TRINZA.

Results

• Overall, 22 patients were included in the study. The mean dose of INVEGA TRINZA was 495 mg.
• After 9 months of treatment with INVEGA TRINZA, 4.6% of patients reported weight gain, and 4% reported a weight gain of >7%.
• The mean percentage variation in body weight from baseline to the end of the study was 4.2%.

Clark et al (2024)⁹ reported the 36-month follow-up analysis of INVEGA TRINZA monotherapy in 97 patients (mean [SD] age, 43.5 [11.1] years; male, 71.1%) with schizophrenia who were evaluated in a retrospective, observational study conducted between November 2016 and September 2018 in London. The primary endpoints were rates related to the continuation of INVEGA TRINZA therapy or relapse by the end of the observational period.

• Five patients (5%) relapsed, all within the first 18 months of the observation period.
• Out of 33 (34.0%) patients who discontinued INVEGA TRINZA, 8 (24.2%) were due to adverse effects, including 4 due to weight gain.

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 10 May 2024.