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.^1,2 Clinical monitoring of weight is recommended.^3,4
• A phase 3, 12-month, randomized, double-blind (DB), active-controlled, parallel-group noninferiority study evaluated the efficacy of INVEGA HAFYERA (N=478) relative to INVEGA TRINZA (N=224) in delaying time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA.²
  • In the DB phase of the clinical trial, weight increase was reported in 8.4% and 7.6% of patients in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively.²
  • 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.⁵
  • 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.⁶
• In a 2-year, single-arm, open-label extension (OLE) of the phase 3, DB, noninferiority study, weight increase was reported in 4 (7.0%) patients treated with INVEGA TRINZA and 5 (4.1%) patients treated with INVEGA HAFYERA during the DB phase who went on to receive INVEGA HAFYERA in the OLE phase.⁷

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 milligrams of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq to mg is 1.56.³

• 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 place patients at increased cardiovascular risk.⁸ 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.^4,8 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.⁸ Rapid weight gain may be observed over the first 2-3 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.⁸ 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 ≥25.⁴ Weight and BMI measurements should be checked routinely (at every visit or approximately every 4 weeks), especially for the first 3-6 months after treatment initiation or change in therapy and every 3 months thereafter.^4,8 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).⁴

CLINICAL DATA

Noninferiority Trial

A phase 3, randomized, DB, active-controlled, parallel-group, multicenter, noninferiority trial was conducted 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.² See Figure: Study Design.

Results

In the open-label (OL) phase, 1.3% of patients experienced treatment-emergent adverse events (TEAEs) related to weight gain, including weight increase, increased appetite, and waist circumference increased. In the DB phase, TEAEs related to weight gain were reported in 9.2% and 8.0% of patients in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively.²

During the OL phase, weight increase was reported in 1% of patients and led to study drug discontinuation in 0.1% of patients. During the DB phase, weight increase was reported in 8.4% and 7.6% of patients in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively. No patients discontinued study drug due to weight increase during the DB phase.²

The mean body weight change and number of subjects with weight percent change ≥7% from DB baseline to DB end point are presented in Table: Weight Changes from DB Baseline to DB End Point.⁹

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

Giron-Hernandez et al (2023)⁵ 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)⁶ 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.

OLE Phase of the Noninferiority Study

Najarian et al (2023)⁷ conducted a 2-year, single-arm, OLE study to evaluate the long-term safety, efficacy, and tolerability of INVEGA HAFYERA in 178 patients who remained relapse free in the DB study and elected to continue treatment with INVEGA HAFYERA in the OLE phase. Data was reported separately for patients who were treated with either INVEGA TRINZA (n=57) or INVEGA HAFYERA (n=121) in the DB phase before transitioning to INVEGA HAFYERA in the OLE phase. In the OLE phase, weight increase was reported in 4 (7.0%) patients in the INVEGA TRINZA/INVEGA HAFYERA group and 5 (4.1%) patients in the INVEGA HAFYERA/INVEGA HAFYERA group.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 17 February 2025.