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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

INVEGA SUSTENNA® (paliperidone palmitate)

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Adverse Event of INVEGA SUSTENNA - Injection Site Reaction/Pain

Last Updated: 09/29/2024

SUMMARY

Pivotal Trials: Injection site reactions were reported in 0% to 10% of INVEGA SUSTENNA-treated patients compared to 2% of placebo (PBO)-treated patients in four fixed-dose, double-blind, PBO-controlled trials in patients with schizophrenia.¹
According to patient visual analog scale (VAS) scores (0=no pain to 100=unbearable pain), the mean intensity of injection pain decreased from first to last gluteal injection during a 13-week, randomized double-blind, placebo (PBO)-controlled, dose-response study in patients with schizophrenia, in all treatment groups. Occurrences of redness, induration, or swelling were reported by investigators as infrequent and mild, decreasing over time, for both INVEGA SUSTENNA and PBO groups.²
At the end of a long-term, double-blind, randomized, multicenter, PBO-controlled, parallel group study, assessing INVEGA SUSTENNA in delaying time-to-relapse in schizophrenic patients, investigators rated injection site pain as absent for both INVEGA SUSTENNA (81%) and PBO (82%) administered via gluteal injections.³
Deltoid vs Gluteal: In a 25-week, randomized, double-blind, multicenter, cross-over study assessing the safety and tolerability of INVEGA SUSTENNA administered via a deltoid vs gluteal injection to patients with schizophrenia, VAS results revealed that patients experienced more intense pain following deltoid vs gluteal injections of INVEGA SUSTENNA 78 mg and 117 mg. No differences were detected at the 156 mg dose. Additionally, a higher percentage of patients experienced swelling and induration after deltoid administration vs gluteal administration.⁴
During a 53-week, phase 3, double-blind trial assessing the noninferiority of INVEGA SUSTENNA to risperidone long-acting injection (RLAI) (both administered via gluteal injections) in the long-term treatment of schizophrenia, the frequency of treatment-emergent injection site pain was similar for both groups (2%-3%).⁵
Treatment-emergent injection site pain occurred in 5.1% of patients administered INVEGA SUSTENNA (initiation doses administered via the deltoid muscle; subsequent doses administered via deltoid or gluteal muscle) and 0.8% administered RLAI (gluteal administration only) during a 13-week, randomized, double-blind, double-dummy, flexible-dose, multicenter study in patients with schizophrenia.⁶
Mild injection site pain was similar between INVEGA SUSTENNA and RLAI and overall local injection site tolerability was good during a 13-week, rater-blinded study assessing non-inferiority of INVEGA SUSTENNA (initiation doses administered via the deltoid muscle; subsequent doses administered via deltoid or gluteal muscle) to RLAI (gluteal administration only) in adult Chinese patients with acute schizophrenia.⁴
Case Reports: A case of anaphylactoid reaction was reported in a 19-year-old man who had tolerated five days of treatment with oral risperidone (gradually increased to 2 mg twice daily) and subsequently experienced an anaphylactoid reaction following administration of INVEGA SUSTENNA 234 mg.⁷ In addition, a case report of septic shock and necrotizing deep tissue infection in a patient receiving INVEGA SUSTENNA is summarized for your review.⁸
Prevention/Treatment: 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 associated with INVEGA SUSTENNA.

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 mg of paliperidone palmitate to reflect the commercially available INVEGA SUSTENNA and INVEGA TRINZA dosage strengths in the United States. The conversion factor from mg eq. to mg is 1.56.

INVEGA SUSTENNA doses expressed as 25, 50, 75, 100, and 150 mg eq. are equal to 39, 78, 117, 156, and 234 mg of paliperidone palmitate, respectively.
INVEGA TRINZA doses expressed 546 and 819 mg of paliperidone palmitate are equal to 350 and 525 mg eq., respectively.

CLINICAL STUDIES

Schizophrenia and Schizoaffective Clinical Trial Results

Trial Design	Injection Site Reactions/Pain^a
Double-Blind Pivotal Trials
Gopal (2010)⁹ conducted a 13-week, multicenter, randomized, DB, PBO-controlled, parallel-group, dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA in patients with schizophrenia (n=388, safety analysis set). Following a washout, screening, and tolerability period that lasted for ≤7 days, patients were each randomized to receive one of three fixed doses of INVEGA SUSTENNA (78, 156, or 234 mg) or PBO administered by *gluteal* IM injection on days 1, 8, 36, and 64.	TEAE of injection site pain and injection site induration occurred ≥3% more frequently with INVEGA SUSTENNA 78 mg and 156 mg than with PBO.
Hough (2010)³ conducted a longer term, DB, randomized, multicenter, PBO-controlled, parallel group study examining the efficacy and safety of INVEGA SUSTENNA in delaying time-to-relapse in schizophrenic patients (n=849, transition and maintenance population; n=408, DB safety analysis set). 9-week OL transition phase: INVEGA SUSTENNA 78 mg on day 1 and day 8 followed by adjustable INVEGA SUSTENNA doses (39, 78, or 156 mg) administered every 4 weeks for the rest of the transition period. 24-week OL maintenance phase: Adjustable INVEGA SUSTENNA doses (39, 78, or 156 mg) administered every 4 weeks for the first 12 weeks followed by fixed INVEGA SUSTENNA doses of 39, 78, or 156 mg. every 4 weeks for the last 12 weeks. DB phase: Fixed INVEGA SUSTENNA doses of 39, 78, or 156 mg (n=205) or PBO (n=203) every 4 weeks.	All doses administered IM via gluteal muscle: At the end of the transition and maintenance phase, investigators rated injection site pain as absent in 76-80% of patients. At the end of the DB treatment period, investigators rated injection site pain as absent for both INVEGA SUSTENNA (81%) and PBO (82%) patients.
Kramer (2010)¹⁰ conducted a 9-week, DB, randomized, international study comparing the safety and efficacy between INVEGA SUSTENNA (two fixed doses) and PBO in the treatment of adults with schizophrenia (n=247). Following a 5-day screening/washout phase and a 7-day oral run-in period, patients were randomized to receive *gluteal* IM injections of INVEGA SUSTENNA 78 mg (n=79), INVEGA SUSTENNA 156 mg (n=84), or PBO (n=84), without oral supplementation, on days 1, 8, and 36.	Investigator ratings of local injection site pain were similar between the INVEGA SUSTENNA and PBO groups: Absent: 56-71% Mild: 24-39% Moderate: 2-12% Severe: 0-2% Induration and swelling were reported for ≤10% of patients and were reported more frequently with INVEGA SUSTENNA than with PBO. Redness was primarily absent or mild in all treatment groups. The incidence of redness was greater with INVEGA SUSTENNA 156 mg than with INVEGA SUSTENNA 78 mg after the injection on day 1; the incidence was similar between both INVEGA SUSTENNA groups, but higher than PBO after injections on days 8 and 36.
Nasrallah (2010)² conducted a 13-week, multicenter, randomized, DB, PBO-controlled, parallel group, dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA in patients with schizophrenia (n=517, safety analysis set). Following a ≤7-day screening, washout, and tolerability period, patients were randomized to one of three fixed INVEGA SUSTENNA doses (39, 78, or 156 mg) or PBO administered by *gluteal* IM injection on days 1, 8, 36, and 64.	Patient-rated injection site pain scores: INVEGA SUSTENNA 39 mg: day 1, 6.9 mm; day 92, 0.7 mm INVEGA SUSTENNA 78 mg: day 1, 6.6 mm; day 92, 3.5 mm INVEGA SUSTENNA 156 mg: day 1, 5.8 mm; day 92, 1.4 mm PBO: day 1, 8.3 mm; day 92, 1.2 mm During the study, investigators reported injection site pain in INVEGA SUSTENNA -treated patients as absent (86-100%), mild (0-12%), or moderate to severe (0-2%). Investigators reported similar ratings for injection site pain in INVEGA SUSTENNA and PBO treated patients. Investigator-reported occurrences of redness, induration, or swelling were infrequent, mild, and decreased over time; the incidence was similar between INVEGA SUSTENNA and PBO groups.
Pandina (2010)¹¹ and Haskins (2009)¹² conducted a 13-week, multicenter, randomized, DB, PBO-controlled, international dose response INVEGA SUSTENNA study in patients experiencing an acute exacerbation of established schizophrenia (n=652). Following a ≤7-day screening, washout, and tolerability period, patients were randomized to one of three INVEGA SUSTENNA treatment arms or PBO: Initiation Dose Day 1 (deltoid IM inj) INVEGA SUSTENNA 234 mg (n=488); PBO (n=164) Fixed Dose Day 8, 36, and 64 (*deltoid or gluteal* IM inj) INVEGA SUSTENNA 234 mg (n=163); INVEGA SUSTENNA 156 mg (n=165); INVEGA SUSTENNA 39 mg (n=160); PBO (n=164)	Compared to the PBO group, the INVEGA SUSTENNA group (dose groups receiving 39 mg, 156 mg, and 234 mg combined) experienced more treatment-emergent injection site pain (4% vs 8%, respectively). Incidence of injection site pain as a TEAE during intervals after treatment initiation, n (%): Days 1-7: PBO: 6 (3.8%); INVEGA SUSTENNA 234 mg: 32 (6.7%) Days 8-14: PBO: 1 (0.6%); INVEGA SUSTENNA 39 mg: 1 (0.7%); INVEGA SUSTENNA 156 mg: 4 (2.5%); INVEGA SUSTENNA 234 mg: 2 (1.3%) Days 15-36: PBO: 2 (1.3%); INVEGA SUSTENNA 39 mg: 0; INVEGA SUSTENNA 156 mg: 0; INVEGA SUSTENNA 234 mg: 1 (0.6%)
Fu et al¹³^-¹⁵ conducted an international, long-term, DB, PBO-controlled, randomized-withdrawal study of INVEGA SUSTENNA in patients with schizoaffective disorder. Study Phases 1 to 7-day screening period, during which patients received oral tolerability testing if necessary 13-week, OL, lead-in period, during which patients received INVEGA SUSTENNA (234 mg on day 1 and 156 mg on day 8 in the deltoid muscle, followed by flexible doses [78-234 mg] on days 36, 64, and 92), as monotherapy or as an adjunct to, stable doses of their adjunctive MS or AD medications 12-week, OL, fixed-dose phase, during which patients who met predefined stabilization criteria received INVEGA SUSTENNA once every 4 weeks, at the final dose received during the lead-in period 15-month, DB phase, during which patients who maintained stability based on predefined criteria were randomized to PBO or a fixed dose of INVEGA SUSTENNA	Patient Characteristics The last dose of INVEGA SUSTENNA at the end of the OL phase was 78 mg in 2.7% of patients, 117 mg in 7.3% of patients, 156 mg in 52.8% of patients, and 234 mg in 37.2% of patients. The mean average dose was similar for patients receiving adjunctive therapy and monotherapy.¹⁶ The INVEGA SUSTENNA dose distribution during the DB phase: 78 mg (4.9%), 117 mg (9.8%), 156 mg (47%) or 234 mg (38.4%) doses. OL: From baseline to end of the OL phase, injection site pain was reported in 10.6% (n=71) of patients. DB: Injection site pain or reaction was reported in two patients from each treatment group.¹⁵
Post Hoc Analysis of the Pivotal Trials^b
Kern Sliwa (2011)¹⁷ conducted post hoc analyses examining the severity of injection site pain of INVEGA SUSTENNA compared with other injectable antipsychotics in subjects with schizophrenia. *Sources: 1) Randomized crossover study (Hough 2009) of INVEGA SUSTENNA injections in the deltoid or gluteal* muscle (n=252). 2) DB, randomized study (Pandina 2011) comparing INVEGA SUSTENNA and RLAI (n=1220). 3) Indirect comparison of *gluteal* injection site pain two days after the injection in a first-generation depot study (n=34) (Bloch 2001)¹⁸ vs an OL, multicenter, parallel-group phase 1 INVEGA SUSTENNA study. *Treatment: 1) See Hough (2009)⁴ study groups. 2) See Pandina (2011)⁶ study groups. 3) Two study groups: In the first-generation depot study, subjects received gluteal* injections of either haloperidol, fluphenazine, zuclopenthixol, or flupenthixol. In the OL INVEGA SUSTENNA study, subjects were administered 2 injections of 39 mg or 234 mg INVEGA SUSTENNA in the *deltoid or gluteal* muscle.	1) Randomized crossover: Symptoms including pain, redness, swelling, and induration as assessed by the investigator were numerically higher for the deltoid vs gluteal injection. Mean VAS scores reported by patients within 30 minutes of the first INVEGA SUSTENNA injection in the deltoid vs the gluteal muscle: INVEGA SUSTENNA 156 mg: 12.2 vs 12.1, respectively INVEGA SUSTENNA 117 mg: 10.0 vs 8.0, respectively 2) DB, randomized: Mean VAS scores for subjects’ assessment of injection site pain for both INVEGA SUSTENNA and RLAI were highest on the day of the first injection, and decreased at subsequent injections. Mean VAS scores were significantly higher for INVEGA SUSTENNA than for RLAI at 30 minutes after the first injection (24.2, INVEGA SUSTENNA; 18.7, RLAI; least squares mean difference -5.50, P<0.001) and for the last injection (20.0, INVEGA SUSTENNA; 16.0, RLAI; least squares mean difference -4.11, P=0.002). However, the incidence of local injection site redness, swelling, and induration appeared to be similar for both groups and these effects were infrequent and generally mild, as assessed by the study investigators. 3) Indirect comparison: Mean VAS scores 2 days after injection were haloperidol 19.5, zuclopenthixol 15.0, fluphenazine 6.9, and flupenthixol 5.2. Corresponding VAS scores for INVEGA SUSTENNA 39 mg and 234 mg, administered in the gluteal muscle, were 3.2 and 3.0, respectively.
Additional Double-Blind Trials
Weiden (2020)¹⁹ conducted a 26-week, phase 3b DB trial to evaluate the safety and efficacy of a 2-month formulation of AL in patients hospitalized for acute exacerbation of schizophrenia followed by transition to outpatient care (ALPINE). INVEGA SUSTENNA was included as an active control, but the study was not powered for direct comparisons between the randomized groups. The study consisted of a 1-week screening phase followed by an initial 2-week, inpatient DB phase, and an outpatient continuation phase. AL (n=99): AL Nano Crystal Dispersion plus a single 30 mg dose of oral aripiprazole on day 1 followed by AL 1064 mg IM *gluteal* on day 8 and every 8 weeks. INVEGA SUSTENNA (n=101): 234 mg *deltoid* injection on day 1 and 156 mg *deltoid* injection on day 8 followed by 156 mg IM *gluteal* every 4 weeks. The study did not allow for flexible INVEGA SUSTENNA dosing	Through week 25, injection site pain was reported in 17.2% and 24.8% of patients in the AL and INVEGA SUSTENNA groups, respectively. Injection site pain was predominantly mild and occurred with active and PBO injections in both groups. Two patients discontinued treatment due to injection site pain (1 associated with PBO injection) in the AL group and 1 patient discontinued treatment due to injection site pain in the INVEGA SUSTENNA group. Please see the post-hoc analysis of this study for further details on injection site-related AEs.
Savitz (2016)²⁰ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA. 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. During the OL phase, 1429 patients received INVEGA SUSTENNA in the following doses: 234 mg on day 1 (*deltoid* IM); 156 mg on day 8 (*deltoid* IM); flexible doses of 78-234 mg (*deltoid or gluteal* IM) at weeks 5, 9 and 13. Patients in the DB phase received fixed doses of INVEGA SUSTENNA (78, 117, 156 or 234 mg; n=512) or a 3.5 multiple of 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 PBO injections were given monthly when active therapy was not administered. Patients in the INVEGA SUSTENNA vs INVEGA TRINZA group reported a lower rate of injection site-related TEAEs (6% vs 8%, respectively). Both groups rated injection-site tolerability as good. According to investigator evaluations, induration, redness, and swelling were observed in ≤5% of patients in both treatment groups and were primarily mild in nature.
Takahashi (2013)²¹ conducted a 13-week, randomized, DB, PBO-controlled trial assessing the safety and efficacy of INVEGA SUSTENNA in Asian patients with schizophrenia. *Treatment* INVEGA SUSTENNA (n=159): 234 mg on day 1 (*deltoid* IM); 156 mg on day 8 (*deltoid* IM); once-monthly injections of 117 mg (*deltoid or gluteal* IM) on days 36 and 64. PBO (n=164)	The most frequently reported injection site TEAEs (≥2% either treatment group) for INVEGA SUSTENNA vs PBO, respectively were: pain (13.2% vs 6.7%) induration (3.8% vs 2.4%) swelling (2.5% vs 0%)
Turkoz (2010)²² conducted a safety analysis of data from 3 clinical databases of randomized, DB, PBO-controlled studies of paliperidone ER and INVEGA SUSTENNA to determine the RR of individual adverse events for antipsychotic treatment compared with that for PBO in patients with schizophrenia or schizoaffective disorder.	INVEGA SUSTENNA studies (INVEGA SUSTENNA pooled [n=488]; PBO [n=164]): Patients receiving INVEGA SUSTENNA were at greater risk for injection site pain than those receiving PBO, but the difference was not significant (RR: 2.07; 95% CI: 0.89, 4.82).
Hough (2009)⁴ conducted a 25-week, randomized, DB, multicenter, cross-over study assessing the safety and tolerability of INVEGA SUSTENNA administered via a *deltoid or gluteal* IM injection in adults with stable schizophrenia (n=252, safety analysis set). Following a washout, screening, and tolerability period that lasted ≤7 days, patients were randomized to receive one of two injection site sequences. Period 1: Doses administered on days 1, 8, 36, and 64 followed by Period 2: Doses administered on days 92, 120, and 148. GD = gluteal IM inj during period 1 followed by deltoid IM inj during period 2 DG = deltoid IM inj during period 1 followed by gluteal IM inj during period 2	INVEGA SUSTENNA doses: 78 mg: GD (n=40); DG (n=42) 117 mg: GD (n=44); DG (n=40) 156 mg: GD (n=40); DG (n=46) Based upon investigator evaluations, a higher proportion of patients in the DG group appeared to have pain at the injection site following deltoid administration (41% deltoid, 26% gluteus; 90%CI). VAS results revealed that patients experienced more intense pain following deltoid vs gluteal injections of INVEGA SUSTENNA 78 mg and 117 mg. No differences were detected at the 156 mg dose. Higher percentage of patients experienced swelling and induration after deltoid administration for both treatment sequences; however, the number of patients who withdrew from the study was similar across both treatment sequences. Injection site-related TEAEs were reported in 6% of subjects who received deltoid injection and in 4% of subjects who received gluteal injection. The most commonly reported injection site-related TEAE was pain.
Post Hoc Analysis of Additional Double-Blind Trials
Citrome et al (2024)²³ conducted a post hoc analysis of the ALPINE study to evaluate the safety and tolerability of AL and INVEGA SUSTENNA.	Injection site pain on Day 1 was reported in 10.1% of patients in the AL group and 18.8% of patients in the INVEGA SUSTENNA group; injection site pain decreased by the next injections. For the occurrence rate of injection site-related AEs see Table below. Injection Site-Related Adverse Events
	AEs	AL (n=99)		INVEGA SUSTENNA (n=101)
	AEs	AL Injection in GL Muscle, n/N (%)^a	PBO Injection in DL Muscle on Day 1 and Day 8, Otherwise in GL Muscle, n/N (%)^a	INVEGA SUSTENNA Injection in DL Muscle on Day 1 and Day 8, Otherwise in GL Muscle, n/N (%)^a	PBO Injection in GL Muscle, n/N (%)^a
	Day 1 injections (AL_NCD or INVEGA SUSTENNA 234 mg and PBO)
	Any injection site reaction^b	11/99 (11.1)	6/99 (6.1)	20/101 (19.8)	4/101 (4.0)
	Day 8 injections (AL 1064 mg or INVEGA SUSTENNA 156 mg and PBO)
	Any injection site reaction^c	8/87 (9.2)	2/87 (2.3)^d	16/95 (16.8)	1/95^d (1.1)
	Day 36 injection (PBO or INVEGA SUSTENNA 156 mg)
	Any injection site reaction^d	0	1/72 (1.4)	0	0
	Day 120 injection (AL 1064 mg or INVEGA SUSTENNA 156 mg)
	Any injection site reaction^d	1/57 (1.8)	0	0	0
	Note: N, number of patients who received an injection; n, number of patients reporting an event ^aPercentages are based on the number of patients for each injection (N). ^bPrimarily included injection site pain; other less commonly occurring injection site reactions (≤1%) were blister, injection site erythema, injection site hypoesthesia, injection site induration, muscle swelling, and myalgia. ^cPrimarily included injection site pain; other less commonly occurring injection site reactions (≤1.1% to ≤2.5%) were injection site induration, injection site swelling, injection site hypoesthesia, injection site pruritus, and injection site reaction. ^dOnly included injection site pain.
Comparison to Risperidone Long-Acting Injection
Fleischhacker (2012)⁵ conducted a 53-week, phase 3, DB trial assessing the noninferiority of INVEGA SUSTENNA to RLAI in the long term treatment of schizophrenia (n=747, safety analysis set; mean age: 41 years; 59% men). INVEGA SUSTENNA (n=379): *gluteal* IM injections on days 1 and 8 (78 mg), followed by flexible doses of 39-156 mg every 4 weeks. To maintain blinding, patients received PBO injections every month as well as oral PBO supplementation during the first 4 weeks of treatment and for up to 3 weeks after each dose increase. RLAI (n=368): *gluteal* IM PBO injection on day 1 and 25 mg RLAI on days 8 and 22, followed by flexible doses of 25, 37.5 or 50 mg RLAI administered every 2 weeks. Patients received supplementation with oral risperidone (1–6 mg/day) during the first 4 weeks of treatment and for up to 3 weeks after every dose increase.	In the safety analysis set, all 27 *gluteal* injections were received by 40% (n=151/379) of INVEGA SUSTENNA and 47% (n=174/368) of RLAI patients during the DB phase. The frequency of treatment-emergent injection site pain was similar for both groups (2%-3%). The number of patients with moderate or severe redness, pain or swelling at the injection site (investigators' evaluations) was lower at endpoint, for both treatment groups, compared to baseline. From baseline to endpoint, mean VAS scores decreased for both INVEGA SUSTENNA (7.8 to 3.4, respectively) and RLAI (9.6 to 3.4, respectively). No patient discontinued treatment due to injection site pain.
Pandina (2011)⁶ conducted a 13-week, randomized, DB, double-dummy, active-controlled, parallel-group, flexible-dose, multicenter study comparing efficacy and safety between INVEGA SUSTENNA and RLAI in the treatment of patients with schizophrenia (n=1214, safety analysis set). INVEGA SUSTENNA (n=606): 234 mg *deltoid* injection of INVEGA SUSTENNA on day 1 followed by a 156 mg *deltoid* injection on day 8; thereafter, patients received flexibly dosed INVEGA SUSTENNA injections on days 36 and 64 in either the *deltoid or gluteal* muscle (PBO injections were matched to RLAI on day 8 and every 2 weeks thereafter). RLAI (n=608): 25 mg RLAI on days 8 and 22, followed by 25 or 37.5 mg on days 36 and 50; thereafter, patients received flexible doses of 25, 37.5, or 50 mg on days 64 and 78, all in the *gluteal* muscle (PBO injections matched those of paliperidone palmitate on days 1, 8, 36, and 64). Oral supplementation was with flexible RIS (1-6 mg) for the first 28 days.	TEAEs of injection site pain occurred in 5.1% of patients with INVEGA SUSTENNA and 0.8% with RLAI.
Li et al (2011)⁴ conducted a 13-week, randomized, active-controlled, parallel-group, multicenter, OL, rater-blinded study assessing non-inferiority of INVEGA SUSTENNA to RLAI in adult Chinese patients with acute schizophrenia (n=452, safety analysis set). Following a ≤7-day screening, washout, and tolerability period, patients were randomized to receive INVEGA SUSTENNA or RLAI: INVEGA SUSTENNA (n=229): *deltoid* IM injection on day 1 (234 mg) and day 8 (156 mg) with the optional injection site of the *gluteal* muscle for day 36 (78 or 156 mg) and day 64 (78, 156, or 234 mg). RLAI (n=223): *gluteal* IM injection on days 8 and 22 (25 mg); flexible doses every 2 weeks thereafter: days 36 and 50 (25 or 37.5 mg), days 64 and 78 (25, 37.5, or 50 mg). Oral RIS supplementation occurred during the first 4 weeks (1-6 mg/day). Additional oral RIS 1-2 mg/day was allowed during the 3-week period after each dosage increase.	Most injection site-related adverse events were considered mild and included: Injection site induration: INVEGA SUSTENNA 0.9%; RLAI 0% Injection site pain: INVEGA SUSTENNA 2.6%; RLAI 0.4% Injection site swelling: INVEGA SUSTENNA 1.7%; RLAI 0% According to investigator assessments, induration, swelling, and redness were observed in <12% of patients in both treatment groups and were overall mild. In both treatment groups, mean VAS scores reported by patients were highest on day 1 of injections, with the average intensity decreasing over time. The average intensity of injection site pain did not significantly change over time. Overall, the mild injection site pain was similar between the treatment groups and overall local injection site tolerability was good for both INVEGA SUSTENNA and RLAI.
Rater-Blinded Trials
Alphs (2015)²⁴ conducted a 15-month, prospective, randomized, OL, event monitoring board (EMB)-blinded, multicenter US study (PRIDE: Paliperidone Palmitate Research In Demonstrating Effectiveness) comparing the time to first treatment failure in a community sample of patients with schizophrenia, recently released from incarceration, receiving INVEGA SUSTENNA once monthly or oAPs daily (N=444).	Mean INVEGA SUSTENNA dose, per injection records: 181.3 mg (n=226) Injection site pain was reported in 18.6% (n=42) of patients receiving INVEGA SUSTENNA.
Schreiner (2015)²⁵ conducted a 24-month, randomized, rater-blinded, prospective, OL, international study (PROSIPAL) comparing treatment outcomes, including time to relapse, among patients receiving oAPs vs INVEGA SUSTENNA. Patients in the INVEGA SUSTENNA group were converted to INVEGA SUSTENNA in the following manner: Initial injection of 234 mg on day 1 (*deltoid* IM) 156 mg on day 8 (*deltoid* IM) 117 mg on day 38 (*deltoid or gluteal* IM) Then flexible-dosing (39-234 mg) once monthly (*deltoid or gluteal* IM).	Mean maintenance dose (fourth injection onwards); 91.5% (322/352) received INVEGA SUSTENNA according to appropriate study protocol dosing schedule: 158.7 mg Injection site pain was reported in 6.8% (n=24/352) of INVEGA SUSTENNA patients.
Open-Label Clinical Trials (≥6 months)
PALMFlex is an international, prospective, 6-month, OL study assessing the efficacy and safety of treatment with flexibly dosed INVEGA SUSTENNA in adult patients with acute or nonacute schizophrenia who previously failed treatment with other antipsychotics.²⁶^-²⁸ Transition from Oral Antipsychotics: After tapering off oral antipsychotics over ≤4 weeks, INVEGA SUSTENNA was initiated at 234 mg on day 1 and 156 mg on day 8 (±2 days), both administered IM in the *deltoid* muscle. Patients receiving CLOZ within 3 months of trial initiation were not eligible to participate. Transition from LAI Antipsychotics: For patients receiving long-acting injectables, the first INVEGA SUSTENNA dose (78-234 mg) was administered in place of the next scheduled depot injection. Maintenance: Flexible INVEGA SUSTENNA doses of 78-234 mg were administered monthly thereafter (±7 days).	Acute Schizophrenia switched from Oral Antipsychotics (n=212)²⁶: Injection site pain was reported in 13.7% of patients with acute exacerbation of schizophrenia switched from oral antipsychotics. Nonacute Schizophrenia switched from Oral Antipsychotics (n=593)²⁷: Injection site pain was reported in 12.3% of patients switched from oral antipsychotics. Nonacute Switched from LAI Antipsychotics (RLAI [n=56]; HAL decanoate [n=53], FPT decanoate [n=35], FLU decanoate [n=44], or ZUC decanoate [n=42])²⁸: The percentages of patients reporting injection site pain per LAI switch group were: RLAI: 7.1% FPT decanoate: 2.9% FLU decanoate: 9.1% HAL decanoate: 3.8% ZUC decanoate: 7.1%
Zhang et al (2015)²⁹ conducted a phase 3b, OL, multicenter study evaluating the safety, tolerability, and efficacy of INVEGA SUSTENNA in Asian/Australian patients with recent-onset schizophrenia who previously failed treatment with oral antipsychotics (n=521, ITT/safety population). Dosing: *Deltoid* IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections of 78-234 mg (*deltoid or gluteal* IM).	Mean duration of exposure: 382.6 days. On day 38, 66% of patients received a 117 mg maintenance dose. Injection site pain was one of the most common TEAEs, occurring in 18.6% of patients. Injection site pain intensity decreased over time (days 1-8: 17.1%; days 9-30: 1.3%). Post-Hoc Analyses Si et al (2019)³⁰ conducted a subgroup analysis of the Zhang (2015) trial in Chinese patients (n=108). Injection site pain was reported in 13.9% of patients.
Si et al (2014)³¹ conducted an OL, randomized, parallel group, multicenter study to assess the PK parameters of INVEGA SUSTENNA 39, 156 and 234 mg in Chinese patients with schizophrenia. Treatment Screening phase (up to 21 days): For patients with undocumented tolerability to oral RIS, oral PAL or RLAI, PAL 3 mg/day x 2 consecutive days was administered at least 5 days prior to randomization. OL treatment phase (up to 210 days): Eligible patients were randomized (1:1:1 ratio) to INVEGA SUSTENNA 39, 156 or 234 mg on day 1 via *gluteal* injection. On day 8, the same dose was received via the alternate side of the *gluteal* muscle.	One of the most frequent TEAEs included injection site pain, reported in 8.5% of patients. However, no patients discontinued treatment due to TEAEs. According to investigator evaluations of local injection site symptoms on days 1, 8, 15, 35, and 210, pain was most commonly reported. Patients from all 3 INVEGA SUSTENNA groups experienced slight pain following gluteal injections on days 1 and 8, as determined by patient VAS scores. Mean pain scores were comparable across all treatment groups.
Wakamatsu et al (2013)³² conducted a 57-week, OL, flexible-dose study evaluating the long-term safety and efficacy of INVEGA SUSTENNA in Japanese patients with schizophrenia. Treatment INVEGA SUSTENNA 234 mg on day 1 (*deltoid* IM) INVEGA SUSTENNA 156 mg on day 8 (*deltoid* IM) Followed by flexible once-monthly injections (*deltoid or gluteal* IM)	Patients received a mean INVEGA SUSTENNA dose of 166.8 mg for a mean duration of 238.7 days. During the 49-week observation period, injection site TEAEs were experienced by 22.9% of patients.
Coppola (2012)³³ conducted a 53-week, OL, multidose, multicenter study evaluating the pharmacokinetics and long-term safety and tolerability of INVEGA SUSTENNA 234 mg in adults with stable schizophrenia (n=212, safety analysis set). Following a screening and washout phase of ≤21 days, each patient received a *deltoid* IM injection of INVEGA SUSTENNA 234 mg on day 1. Each patient who tolerated the dose (Treatment A, n=186) received a second *deltoid* IM injection of INVEGA SUSTENNA 234 mg on day 8 and 12 once-monthly injections (*deltoid or gluteal* IM) starting on day 36. Patients who were unable to tolerate the 234 mg dose or unwilling to participate in intensive pharmacokinetic sampling (Treatment B, n=26) received second IM injections of INVEGA SUSTENNA 78-234 mg (flexible dose) on day 8 (deltoid or gluteal muscle) and 12 once-monthly injections starting on day 36 (*deltoid or gluteal* IM).	Injection site pain was reported in 15% of the total study population (14.4% [15/104] of patients who completed the study on 234 mg throughout, and 15.7% [17/108] of patients who did not complete the study on 234 mg throughout). No patients discontinued due to an injection site related adverse event.
Gopal (2011)³⁴ conducted a 52-week, OL extension (OLE) study assessing the long-term safety and efficacy of INVEGA SUSTENNA in patients with schizophrenia following a DB, randomized, multicenter, PBO-controlled, parallel group trial (n=388) (Hough 2010)³ Study Treatment (all doses administered IM via *gluteal* muscle): Patients entering the OLE phase received a total of 12 INVEGA SUSTENNA doses beginning with a 78 mg dose. Every 4 weeks, starting with the second injection, doses were titrated up or down in 39 mg increments to meet clinical needs (INVEGA SUSTENNA 39, 78, 117, or 156 mg doses). Oral supplementation with paliperidone extended-release was permitted for all patients for the first 8 OLE weeks in order to avoid treatment interruption (initiated at 6 mg/day; titrated up/down in 3 mg/day increments within a range of 3-12 mg/day).	*Study Groups* PBO/ INVEGA SUSTENNA (n=153): PBO during DB phase; INVEGA SUSTENNA during OLE phase. INVEGA SUSTENNA / INVEGA SUSTENNA (n=161): INVEGA SUSTENNA during DB and OLE phases. No DB/ INVEGA SUSTENNA (n=74): Patients in transition or maintenance phases entering directly to OLE phase upon DB termination. *Results* Investigators reported only mild redness in patients (≤4%) at OLE endpoint. According to investigator assessments, injection site pain was absent in 82-87% of patients across all treatment groups at OLE endpoint. In all groups, mean patient-rated injection site pain was low at OLE baseline (5.9-9.0 mm on a 100-mm scale) and further reductions were seen at OLE endpoint. In the PBO/ INVEGA SUSTENNA and INVEGA SUSTENNA groups, mean pain of injection was low at OLE baseline (9.5-12.0 mm on 100-mm scale), and further reductions were seen at OLE endpoint; a slight increase was seen in the DB/ INVEGA SUSTENNA group. No patient discontinued treatment because of injection site adverse events.
Case Report
Leung (2015)⁸ reported a case of septic shock and necrotizing deep tissue infection in a patient receiving INVEGA SUSTENNA. A 26-year-old female with a history of schizophrenia had been treated with INVEGA SUSTENNA for 14 months. Due to breakthrough symptoms, INVEGA SUSTENNA 234 mg was prescribed every 3 weeks for the last 3 months along with oral paliperidone 1.5 mg daily. Her last INVEGA SUSTENNA dose was administered in the right *deltoid* muscle, 11 days prior to admission. She presented to the ER with septic shock of unclear etiology. The patient deteriorated over the course of two days in the ICU following treatment with IV fluids and antibiotics (piperacillin/tazobactam and vancomycin). The patient was intubated, and high-dose vasopressors were initiated. Levofloxacin was added to her antibiotic regimen. Due to improved hemodynamics, vasopressors and antibiotics were discontinued on day 6. However, respiratory failure, fever and leukocytosis persisted. Imaging and microbiology were negative.	An abscess on her right deltoid muscle went unidentified until hospital day 10 following indium leukocyte imaging and attempted biopsy. The patient underwent surgical debridement and irrigation and was initiated on vancomycin, meropenem, and clindamycin. A positive stain of Gram-positive cocci resembling Staphylococcus was identified. A wound vacuum assisted closure device was placed and the patient was extubated and transferred to the ICU. Following a 10-day course of daptomycin, the patient was discharged on day 26 with wound care follow-up. The authors noted that the patient’s unrecognized infectious process in the deltoid led to increased ICU resource utilization (increased length of stay; time on ventilator). It was not known until after extubating that the patient was experiencing increasing right shoulder pain 2 days after her last INVEGA SUSTENNA injection. The authors also note that while the exact mechanism in which the infection began is unknown, as with all injection site reactions, administration technique, sterile processes and sources of contamination should be questioned.
^aInjection site assessments were carried out through investigator evaluations of injection site redness, pain, swelling and induration in addition to descriptive analysis of site pain by patients; ^bOnly post hoc analyses focusing on injection site reactions associated with paliperidone palmitate have been included in this reply.Abbreviations: AD, antidepressant; AE, adverse event; AL, aripiprazole lauroxil; AL_NCD, aripiprazole lauroxil NanoCrystal Dispersion; CI, confidence interval; CLOZ, clozapine; DB, double-blind; DL, deltoid; ER, Emergency Room; FLU, fluphenazine; FPT, flupentixol; GL, gluteal; HAL, haloperidol; ICU, Intensive Care Unit; IM, intramuscular; ITT, intent-to-treat; LAI, long-acting injectable; oAP, oral antipsychotics; OLA, olanzapine; OLE, open-label extension; PAL, paliperidone ER; PBO, placebo; PK, pharmacokinetics; RIS, risperidone; RLAI, risperidone long-acting injection; RR, relative risk; TEAE, treatment emergent adverse event; VAS, visual analogue scale (patient rated; 0=no pain, 100=unbearable pain, unless otherwise stated); ZUC, zuclopenthixol

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 27 August 2024.

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