Summary

• A phase 3, 12-month, randomized, double-blind (DB), active-controlled, parallel-group, noninferiority trial was conducted to evaluate the efficacy and safety of INVEGA HAFYERA (N=478) relative to INVEGA TRINZA^® (paliperidone palmitate 3-month) (N=224) in delaying time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA^® (paliperidone palmitate 1-month) or INVEGA TRINZA.¹ 
  • During the DB phase, 12.3% and 4.9% of patients reported injection site-related treatment-emergent adverse events (TEAEs) in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively. The most common injection site-related TEAE reported in the INVEGA HAFYERA vs INVEGA TRINZA groups was injection site pain (7.7% vs 4.0%).¹
  • Investigator-rated induration, redness and swelling were observed in 13% in the INVEGA HAFYERA group and 9% in the INVEGA TRINZA group during the DB phase. Tenderness was higher for patients in the INVEGA HAFYERA group versus the INVEGA TRINZA group (31% vs 19%) during the DB phase.²
  • According to patient ratings of injection-site pain, the average score on a visual analog scale (VAS) of 0 to 100 was 17.2 and 15.0 in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively, at the DB baseline and approximately 5 in both groups at DB endpoint.¹
  • In a post hoc subgroup analysis of patients enrolled in European investigational sites, injection site pain was reported in 5 (4.0%) patients in the INVEGA TRINZA group and 14 (5.4%) patients in the INVEGA HAFYERA group during the DB phase.³
  • In another post hoc subgroup analysis of the Asian population, injection site pain was reported in 2 (7.1%) patients in the INVEGA TRINZA group and 9 (14.5%) patients in the INVEGA HAFYERA group during the DB phase.⁴
• In a 2-year, single-arm, open-label extension (OLE) of the phase 3, DB, noninferiority study, injection site pain was reported in 4 (2.2%) patients on INVEGA HAFYERA.⁵
• INVEGA HAFYERA is intended for gluteal intramuscular use only. Inject slowly, deep into the gluteal muscle. Alternate injections between the 2 gluteal muscles.⁶
• Published literature provides varied recommendations on the maximum injection volume that is recommended for gluteal intramuscular administration (4-5 mL). Because of the proximity of the sciatic nerve and superior gluteal artery to the dorsogluteal site, or the upper outer quadrant of the buttock, locating the precise injection site by palpating the ileum and the trochanter is important.^7-9
• A search of the current literature did not identify any data discussing the use of topical anesthetics, ice/cooling techniques, or warm compresses for the prevention or treatment of injection-site reactions specific to INVEGA HAFYERA. Do not rub the injection site.⁶ It is unknown how such techniques might affect the properties of INVEGA HAFYERA, 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 INVEGA SUSTENNA and INVEGA TRINZA 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, 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, respectively.
• INVEGA HAFYERA doses expressed as 1,092 or 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq, respectively.

CLINICAL STUDIES

Noninferiority Trial¹

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. See Figure: Study Design.^1,10,11

Results

All patients in both treatment groups received injections in the dorsogluteal muscle during the DB phase.¹

• During the DB phase, 12.3% and 4.9% of patients reported injection site related TEAEs in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively.¹
  • The most common (≥2% in either group) injection site-related TEAEs reported during the DB phase in the INVEGA HAFYERA vs INVEGA TRINZA groups was injection site pain (7.7% vs 4.0%).¹ Additional TEAEs related to injection site during the open-label and DB phase are presented in Table: Injection Site-Related TEAEs During the OL and DB Phases.¹
• None of the injection site-related TEAEs were reported as serious, resulted in treatment discontinuation, or required dermatological consultation.^1,12

Investigator Ratings of Injection Site

• Based on investigator evaluations during the DB phase, induration, redness and swelling at the injection site were observed in 13% in the INVEGA HAFYERA group and 9% in the INVEGA TRINZA group.²
• Tenderness was higher for patients in the INVEGA HAFYERA group versus the INVEGA TRINZA group (31% vs 19%) during the DB phase.²

Patient Ratings of Injection Site Pain

• Injection pain was assessed by patients using a VAS within 30 minutes after injection. The average score for the patient’s evaluation of injection pain on a scale of 0 to 100 was 17.2 and 15.0 in the INVEGA HAFYERA and INVEGA TRINZA groups, respectively, at the DB baseline and approximately 5 in both groups at DB endpoint.¹
• Patient assessment of injection site pain decreased from DB baseline to endpoint.¹
• Changes from baseline were generally consistent across treatment groups.¹² See Figure: VAS Scores for Patient Ratings of Injection Site Pain

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

Giron-Hernandez et al (2023)³ 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, injection site pain was reported in 5 (4.0%) patients in the INVEGA TRINZA group and 14 (5.4%) patients in the INVEGA HAFYERA group. Other common injection site-related TEAEs reported in the INVEGA TRINZA group vs the INVEGA HAFYERA group were swelling (0.8% vs 1.5%), induration (1.6% vs 1.5%), discomfort (0.8% vs 0.4%), erythema (0.8% vs 0.4%), edema (0% vs 0.4%), hemorrhage (0% vs 0.4%), musculoskeletal pain (0% vs 0.4%), and pain in extremity (0.8% vs 0.4%).

Richarz et al (2023)⁴ 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, injection site pain was reported in 2 (7.1%) patients in the INVEGA TRINZA group and 9 (14.5%) patients in the INVEGA HAFYERA group. Other common injection site-related TEAEs reported in the INVEGA TRINZA group vs the INVEGA HAFYERA group were swelling (0% vs 3.2%) and pain in extremity (3.6% vs 1.6%). In both groups, mild to moderate tenderness was absent at the DB endpoint vs in <30% of patients in the DB baseline. Additionally, in both groups, the patient-perceived injection site pain was lesser at the DB endpoint vs the DB baseline.

OLE Phase of the Noninferiority Study

Najarian et al (2023)⁵ 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 were reported separately for patients treated with either INVEGA TRINZA (n=57) or INVEGA HAFYERA (n=121) in the DB phase before transitioning to receiving INVEGA HAFYERA in the OLE phase. Injection site pain was reported in 4 (2.2%) patients, and in 1 patient (0.6%) as TEAE, on INVEGA HAFYERA during the OLE phase. Extremity pain was another injection site-related TEAE reported by 2 (1.1%) patients during the OLE phase. In injection site reactions, erythema/redness was absent at baseline and the endpoint; induration/swelling and tenderness were absent or mild at baseline and the endpoint in the majority of patients. Only 1 (0.6%) patient each reported severe induration/swelling and tenderness at the endpoint.

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 09 May 2024.