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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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INVEGA SUSTENNA - Adverse Event - Prolactin Effects

Last Updated: 02/11/2025

SUMMARY

Prolactin (PRL) regulation is complex, involving many different neurochemicals and receptors. The two primary receptors involved in the release of PRL are the dopamine D2 and serotonin (5-HT)_2Areceptors. D2 receptor blockade by paliperidone increases the release of PRL.¹ Paliperidone has a PRL-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of PRL than other antipsychotic drugs.²
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving PRL-elevating compounds.¹ Long-standing hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male subjects.³
Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.⁴
In a long-term maintenance trial of INVEGA SUSTENNA in schizophrenia patients, mean serum PRL levels increased during the transition and maintenance phase by 25.3 ng/mL in women and 9.8 ng/mL in men. In the double-blind phase, levels increased by 12.7 ng/mL in women and 3.7 ng/mL in men receiving INVEGA SUSTENNA and decreased by 16.6 ng/mL in women and 9.2 ng/mL in men receiving placebo (PBO). Potentially PRL-related adverse events (AEs) were reported in 1% and 2% of the PBO and INVEGA SUSTENNA group, respectively.⁵
In a long-term maintenance trial of INVEGA SUSTENNA in patients with schizoaffective disorder, PRL related treatment-emergent adverse events (TEAEs) were reported in 13.9% of women and 7.1% of men receiving INVEGA SUSTENNA compared to 5.8% and 1.2% in the PBO group, respectively. The most common TEAEs with INVEGA SUSTENNA and PBO in women were hyperprolactinemia/blood PRL increase (8.9%, 3.5%), amenorrhea (3.8%, 2.3%), and galactorrhea (3.8%, 1.2%). The most common TEAE with INVEGA SUSTENNA and PBO in men was hyperprolactinemia/blood PRL increase (4.7%, 0%).⁶
During a 15-month, prospective, randomized, open-label, event monitoring board-blinded, multicenter United States (US) study designed to reflect real-world schizophrenia patients, treatments and outcomes, treatment-emergent PRL-related AEs were reported in 23.5% (n=53) and 4.1% (n=9) of INVEGA SUSTENNA and oral antipsychotic patients, respectively.⁷
In a pooled analysis of 10 randomized, double-blind and open-label, PBO and active-controlled trials of INVEGA SUSTENNA in patients with schizophrenia⁵^,⁸^-¹⁷, the incidence of potentially PRL-related AEs in the INVEGA SUSTENNA group was 3.4%, which was significantly higher than that in the PBO group; 2.0% of patients experienced symptomatic PRL-related AEs.¹
PRL levels were also evaluated in a noninferiority trial comparing paliperidone palmitate 3-month (PP3M) to INVEGA SUSTENNA.¹⁸ The overall incidence of PRL-related TEAEs was comparable between the PP3M and INVEGA SUSTENNA groups.
A real-world observational study analyzing 27 patients with schizophrenia reported that switching from risperidone long-acting injectable (LAI) to INVEGA SUSTENNA resulted in a significant reduction in PRL levels in women (n=5; P<0.001) with no change in men over a 6-month follow-up period. However, there were no significant changes in sexual dysfunction and sexual functioning in either gender over the same period.¹⁹
A real-world observational study reported that of all discontinuations of INVEGA SUSTENNA due to poor tolerability, 9% (3/33) were due to hyperprolactinemia.²⁰
Post hoc analyses and case series are not included in this response.

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents (mg eq.) 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 dosage strengths available 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.

BACKGROUND

PRL is a 199-amino acid polypeptide hormone that is secreted by the lactotroph cells in the anterior pituitary under the inhibitory control of D₂ receptors. Many antipsychotics, conventional and atypical, which block dopamine receptors in the tuberoinfundibular pathway of the hypothalamus, can increase PRL secretion.²¹^,²²

Paliperidone has a PRL-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of PRL than other antipsychotic drugs.²

Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male subjects.³ In the absence of hypogonadism, there is a lack of consistent evidence to establish whether antipsychotic-induced hyperprolactinemia is an independent risk factor for bone loss and osteoporosis.³ While individuals with schizophrenia are known to have an increased risk for low bone mineral density and osteoporosis, prospective clinical trials to differentiate between etiological mechanisms and effects of disease and treatment have not been conducted.

Management of Hyperprolactinemia

Asymptomatic hyperprolactinemia

Most guidelines recommend against treating asymptomatic hyperprolactinemia induced by antipsychotics.²¹

Symptomatic hyperprolactinemia

The recommendations for the management of symptomatic hyperprolactinemia may include, reducing the dose of the PRL raising agent, switching to a low potency or PRL sparing agent, adding a full or partial dopamine agonist, or discontinuing the PRL elevating agent. Treatments noted with various degrees of support include aripiprazole, cabergoline, bromocriptine, amantadine, estrogen or testosterone, and metformin.²¹^-²³

Two separate algorithms, specific to male and female patients for the management of hyperprolactinemia, are also described in the publication.²¹

Concomitant use with aripiprazole

Aripiprazole as a substitute or in combination with the primary antipsychotic if aripiprazole monotherapy is not achievable may be considered; however, caution should be exercised when combination therapy is utilized as the primary antipsychotic’s efficacy might be reduced due to partial agonism by aripiprazole at D₂ receptors, leading to competitive receptor occupancy.²¹

CLINICAL STUDIES

Clinical Studies

Trial Design	PRL Changes
SCHIZOPHRENIA
Double-Blind Trials including Open-Label Extensions
Hough et al (2010)⁵ 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 following an initial 9-week, OL transition phase and 24-week, OL maintenance phase (n=849, transition and maintenance population; n=408, DB safety analysis set). Dosing Schedule (All doses administered IM via gluteal muscle): 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.	PRL Changes During the OL transition and maintenance phases, mean PRL levels increased by 9.8 ng/mL in males and by 25.3 ng/mL in females. Mean Change in PRL Levels from DB Baseline to Endpoint: PBO: males, -9.2 ng/mL; females, -16.6 ng/mL INVEGA SUSTENNA: males, 3.7 ng/mL; females, 12.7 ng/mL PRL-Related TEAEs PRL-related TEAEs during the transition and maintenance phases occurred in 3% of patients. PRL-related TEAEs during the DB phase occurred in 2% of INVEGA SUSTENNA-treated patients and in 1% of PBO-treated patients.
Gopal et al (2011)¹³ conducted a 52-week, OLE study assessing the long-term safety and efficacy of INVEGA SUSTENNA in 388 patients with schizophrenia (Hough 2010).⁵ Study Treatment All patients received gluteal injections of INVEGA SUSTENNA beginning with a 78 mg dose followed by flexible dosing (39, 78, 117, or 156 mg) once every 4 weeks for 12 injections. 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.	Mean Changes in PRL Levels from OLE Baseline to Endpoint PBO/INVEGA SUSTENNA: males, 7.2 ng/mL; females, 17.0 ng/mL INVEGA SUSTENNA/INVEGA SUSTENNA: males, -2.6 ng/mL; females, -3.1 ng/mL No DB/INVEGA SUSTENNA: males, -0.7 ng/mL; females, 6.6 ng/mL Incidence of PRL Levels >2 Times ULN at Any Time During OLE PBO/INVEGA SUSTENNA: males, 30%; females, 63% INVEGA SUSTENNA/INVEGA SUSTENNA: males, 29%; females, 73% No DB/INVEGA SUSTENNA: males, 25%; females, 76% PRL-Related TEAEs PRL elevations, occurred in 13 patients (primarily females); however, no patient discontinued treatment because of these TEAEs. Most common were amenorrhea (n=6) and galactorrhea (n=3).
Pandina et al (2011)¹⁷ conducted a 13-week, randomized, DB, double-dummy, active-controlled, parallel-group, multicenter study assessing non-inferiority of INVEGA SUSTENNA to RLAI in the treatment of patients with schizophrenia (n=1214, safety analysis set). INVEGA SUSTENNA (n=606): Deltoid injection of INVEGA SUSTENNA 234 mg on day 1 followed by a 156-mg deltoid injection on day 8; thereafter, patients received flexibly dosed INVEGA SUSTENNA injections on days 36 (78 or 156 mg) and 64 (78, 156, or 234 mg) in either the deltoid or gluteal muscle. RLAI (n=608): RLAI 25 mg 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. Oral supplementation with RIS (1-6 mg) was administered for the first 28 days. Optional supplementation with RIS was permitted under certain circumstances.	PRL Changes Mean increase in PRL levels (ng/mL) from baseline to endpoint: INVEGA SUSTENNA: females: 21.8; males: 9.38 RLAI: females: 15.6; males: 6.0 PRL-Related TEAEs The most common potentially PRL-related TEAEs were erectile dysfunction (4 males in the INVEGA SUSTENNA group and 3 males in the RLAI group) and amenorrhea (4 females in the INVEGA SUSTENNA group and 4 females in the RLAI group).
Gopal et al (2010)¹² conducted a 13-week, multicenter, randomized, DB, PBO-controlled, dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA (78, 156, or 234 mg), administered via gluteal injection on days 1, 8, 36 and 64, in patients with schizophrenia (n=388, safety analysis set).	PRL Changes PBO: males, 1.2 ng/mL; females, -11.21 ng/mL INVEGA SUSTENNA 78 mg: males, 7.13 ng/mL; females, 32.04 ng/mL INVEGA SUSTENNA 156 mg: males, 15.10 ng/mL; females, 40.17 ng/mL INVEGA SUSTENNA 234 mg: males, 15.21 ng/mL; females, 62.33 ng/mL Potential PRL-Related TEAEs occurred in 1 patient who received INVEGA SUSTENNA 78 mg (breast hypertrophy), in 1 patient who received INVEGA SUSTENNA 156 mg (erectile dysfunction), and in 2 patients who received PBO (erectile dysfunction, galactorrhea).
Kramer et al (2010)¹⁰ conducted a 9-week, DB, randomized, international study comparing the safety and efficacy between INVEGA SUSTENNA (2 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.	PRL Changes Median PRL levels increased during the oral paliperidone run-in period. Although PRL levels decreased from baseline to endpoint of DB treatment period, they remained above pre-dose levels in INVEGA SUSTENNA-treated patients. PRL levels decreased to pre-dose values in PBO-treated patients. Potential PRL-Related TEAEs occurred in 3 INVEGA SUSTENNA-treated patients (erectile dysfunction, galactorrhea, and amenorrhea) and 1 PBO-treated patient (amenorrhea).
Pandina et al (2010)¹⁶ and Haskins et al (2009)²⁴ conducted a 13-week, phase 3, randomized, DB, PBO-controlled, international dose response INVEGA SUSTENNA study in patients experiencing an acute exacerbation of established schizophrenia (n=652). *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)	PRL Changes Mean PRL levels increased in all INVEGA SUSTENNA groups from baseline to endpoint, with larger increases in females (4.72 ng/mL to 37.24 ng/mL) than in males (3.73 ng/mL to 13.15 ng/mL). The highest increases were observed for each sex in the 234-mg dose group. Mean PRL levels decreased in the PBO-treated group. PRL-Related TEAEs occurred in 3 INVEGA SUSTENNA-treated patients (ejaculation disorder, loss of libido, and galactorrhea) and 1 PBO-treated patient (ejaculation disorder).
Nasrallah et al (2010)⁸ conducted a 13-week, phase 3, multicenter, randomized, DB, PBO-controlled, parallel group, international dose-response study evaluating the efficacy and safety of 3 fixed doses of INVEGA SUSTENNA (39, 78, or 156 mg), administered by gluteal IM injection on days 1, 8, 36, and 64, in patients with schizophrenia (n=517, safety analysis set).	PRL Changes Patients receiving INVEGA SUSTENNA had higher frequencies of and greater dose-related increases in PRL levels from baseline to endpoint than those receiving PBO. Mean Changes in PRL Levels from Baseline to Endpoint PBO: males, -2.1 ng/mL; females, -8.8 ng/mL INVEGA SUSTENNA 39 mg: males, 4 ng/mL; females, 9.3 ng/mL INVEGA SUSTENNA 78 mg: males, 6.8 ng/mL; females, 35.1 ng/mL INVEGA SUSTENNA 156 mg: males, 10.4 ng/mL; females, 43.6 ng/mL PRL-Related TEAEs INVEGA SUSTENNA: 1-2%; PBO: 1% Included erectile dysfunction (PBO, 1%; INVEGA SUSTENNA 156 mg, 1%); galactorrhea (INVEGA SUSTENNA 156 mg, 1%); decreased libido (PBO, 1%); and sexual dysfunction (INVEGA SUSTENNA 78 mg, 1%; INVEGA SUSTENNA 156 mg, 2%).
Hough et al (2009)¹⁵ 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). 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). 1) GD (Gluteal IM inj during period 1 followed by Deltoid IM Inj during period 2) 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) PRL Changes Mean PRL levels increased in all INVEGA SUSTENNA groups, from baseline to endpoint, with larger increases occurring in females (0 ng/mL to 43.1 ng/mL, respectively) compared to males (5.8 ng/mL to 16.7 ng/mL, respectively). Larger increases in PRL were observed in the 117 and 156 mg dosing groups, compared to the 78 mg dose. PRL-Related TEAEs Only 2 TEAEs, potentially related to increased PRL levels, were observed (galactorrhea and decreased libido). Both occurred during period 1.
Additional Double-Blind Trials
Savitz et al (2016)¹⁸ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of PP3M and INVEGA SUSTENNA. The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase. 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 at the following doses: Day 1/Day 8: 234 mg/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 pre-defined 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 PP3M (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 PP3M group PBO injections were given monthly when active therapy was not administered.	Mean Change in Serum PRL Levels (µg/L): OL Baseline to OL Endpoint: INVEGA SUSTENNA: males, 7.65; females, 18.56 DB Baseline to DB Endpoint: PP3M: males, -1.28; females, -3.37 DB Baseline to DB Endpoint: INVEGA SUSTENNA: males, 0.45; females, 0.69 Percentage (%) of Potentially PRL-related TEAEs During OL and DB Phases for OL-INVEGA SUSTENNA (N=1429), PP3M (n=504) and INVEGA SUSTENNA (n=512) patients, respectively: galactorrhea (1.2; 0.6; 1.0); sexual dysfunction (0.3; 0.4; 0); libido decreased (0.2; 0.2; 0); anorgasmia (0.1; 0.2; 0.2); breast enlargement (0.1; 0.2; 0); breast pain (0.1; 0.2; 0) Percentage (%) of Potentially PRL-related TEAEs During OL and DB Phases for OL-INVEGA SUSTENNA (n=782), PP3M (n=258) and INVEGA SUSTENNA (N=281) Male patients, respectively: gynecomastia (0.4; 0.8; 0); erectile dysfunction (0.1; 0.4; 0.4) Percentage (%) of Potentially PRL-related TEAEs During OL and DB Phases for OL-INVEGA SUSTENNA (n=647), PP3M (n=246) and INVEGA SUSTENNA (n=231) Female patients, respectively: amenorrhea (2.6; 3.3.; 1.7); irregular menstruation (1.4; 2.0; 1.3) Males in the INVEGA SUSTENNA group experienced treatment-emergent abnormally high PRL levels at a greater rate than males in the PP3M group (45% vs. 39%; OL baseline to DB). Females in both the INVEGA SUSTENNA and PP3M groups experienced a similar percentage of high PRL levels (32% vs. 33%; OL baseline to DB).
McEvoy et al (2014)²⁵ conducted the ACLAIMS trial, a DB, randomized, multisite, parallel-group US clinical trial comparing the effectiveness of INVEGA SUSTENNA vs HAL decanoate for the maintenance treatment of schizophrenia or schizoaffective disorder. LAI treatment (≤24 months): INVEGA SUSTENNA (n=147): Initiation doses, IM deltoid (234 mg on day 1; 156 mg on day 8); Maintenance doses, IM deltoid or gluteal (117 mg monthly) HAL decanoate (n=147): Initiation doses, IM deltoid (50 mg on day 1; 50 mg on day 8); Maintenance doses, IM deltoid or gluteal (75 mg on days 28 and 56, then 50 mg monthly)	Mean monthly doses of INVEGA SUSTENNA and HAL decanoate ranged from 129-169 mg and 67-83 mg, respectively. Patients were followed for a median of 488 days. Highest mean PRL levels (SI unit conversion factor, multiply by 43.478 for pmol/L) were significantly higher for INVEGA SUSTENNA vs HAL decanoate patients: Males: INVEGA SUSTENNA (34.56 μg/L); HAL decanoate (15.41 μg/L); P<0.001 Females: INVEGA SUSTENNA (75.19 μg/L); HAL decanoate (26.84 μg/L); P<0.001
Takahashi et al (2013)²⁶ conducted a 13-week, randomized, DB, PBO-controlled trial assessing the safety and efficacy of INVEGA SUSTENNA in Asian patients with schizophrenia (N=323; mean age: 45 years; 57% male). 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 IM or gluteal IM) on days 36 and 64. PBO (n=164)	Mean duration of INVEGA SUSTENNA and PBO exposure was 87 and 50 days, respectively. INVEGA SUSTENNA: Mean PRL levels (ng/mL) remained stable at baseline and endpoint for males (30.57 vs 30.72, respectively) and slightly increased at endpoint for females (68.73 vs 79.36, respectively). PBO: Irrespective of gender, an overall decrease in mean PRL level was observed. One patient in the PBO group experienced a PRL-related TEAE (irregular menstruation).
Open-label Rater-Blinded Studies
Wang et al (2024)²⁷ conducted a 49-week, prospective, randomized, active-controlled, OL, rater-blinded, multicenter study in China between November 2017 and June 2020 to evaluate the impact of INVEGA SUSTENNA vs OAPs on violent behavior in patients with schizophrenia and aggressive tendencies. A total of 134 patients (mean age, 39.1 years; male, 52.2%) were randomized to receive either OAPs (n=67; risperidone, aripiprazole, ziprasidone, olanzapine, quetiapine, and amisulpride) or INVEGA SUSTENNA (n=67; on-label initiation followed by once-monthly injections of flexible dosing range of 117 to 234 mg [deltoid IM or gluteal IM]).	Of the 134 patients, 104 (77.6%) completed the study (INVEGA SUSTENNA group, n=59; OAP group, n=45). The duration of maintenance treatment was significantly different between the groups: INVEGA SUSTENNA group, 44.9 (95% CI, 42.2-47.6) weeks; OAP group, 37.1 (95% CI, 38.5-43.6) weeks; P=0.002 PRL-related TEAEs In the INVEGA SUSTENNA group, 45 patients (70.3%) experienced hyperprolactinemia; 9 patients (14.1%) experienced amenorrhea. In the OAP group, 42 patients (62.7%) experienced hyperprolactinemia; 7 patients (11.0%) experienced amenorrhea. There was no significant difference in PRL-related TEAEs between the groups (P>0.05).
Alphs et al (2015)⁷ conducted a 15-month, prospective, randomized, OL, EMB-blinded, multicenter US study (PRIDE) designed to reflect real-world schizophrenia patients, treatments and outcomes. The clinician and patient reviewed the list of available OAPs (aripiprazole, HAL, OLA, paliperidone, perphenazine, quetiapine and RIS) before randomization and could preselect up to 6 from the list based on prior experience. Patients were stratified on the basis of their selection of OAP treatments and randomly assigned to flexibly dosed INVEGA SUSTENNA (78-234 mg) or flexibly dosed OAP therapy.	A treatment-emergent PRL-related AE was reported in 23.5% (n=53) and 4.1% (n=9) of INVEGA SUSTENNA and OAP patients, respectively. The most common (>5%) PRL-related AEs in males receiving INVEGA SUSTENNA (n=193) or OAPs (n=190), respectively were: erectile dysfunction (8.8%; 0%) and decreased libido (6.7%; 1.6%). The most common (>5%) PRL-related AEs in females receiving INVEGA SUSTENNA (n=33) or OAPs (n=28), respectively were: amenorrhea (15.2%; 3.6%), galactorrhea (15.2%; 0%), irregular menstruation (6.1%; 3.6%), hyperprolactinemia (6.1%; 3.6%) and increased blood PRL (6.1%; 0%).
Huang (2017)²⁸ conducted a randomized, 13-week, rater-blinded study evaluating the metabolic effects and efficacy of INVEGA SUSTENNA and oral OLA in Han Chinese patients with first-episode schizophrenia. INVEGA SUSTENNA (n=28): Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by deltoid or gluteal injection on days 36 (78 or 156 mg) and 64 (78 to 234 mg). OLA (n=29): Fixed 5 mg daily x 1 week followed by flexible dosing according to efficacy and tolerability.	Mean doses of INVEGA SUSTENNA and OLA at endpoint were 201.0 mg and 17.8 mg, respectively. PRL Changes Significant increases in PRL occurred in both treatment groups with greater increases observed in the INVEGA SUSTENNA vs OLA group from baseline to endpoint (P=0.025). PRL (µg/L) baseline/endpoint: INVEGA SUSTENNA (n=26): 26.76/58.15 (P=0.002) OLA (n=25): 23.80/27.65 (P<0.001) PRL-Related TEAEs: No significant between group differences (INVEGA SUSTENNA n=4; OLA n=1; P=0.148)
Li (2011)⁹ conducted a 13-week, phase 3, randomized, active-controlled, parallel-group, multicenter, OL, rater-blinded study assessing non-inferiority of INVEGA SUSTENNA to RLAI in Chinese patients with acute schizophrenia (n=452, safety analysis set). 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 days 36 (78 or 156 mg) and 64 (78 to 234 mg). RLAI (n=223): Gluteal IM injection on days 8 and 22 (25 mg); flexible doses of 25 or 37.5 mg on days 36 and 50; and flexible doses of 25 to 50 mg every 2 weeks thereafter beginning on day 64. Daily oral RIS supplementation occurred during the first 4 weeks (2 mg on day 1 and flexible doses of 1 to 6 mg on days 2 through 28). Additional oral RIS 1 to 2 mg was allowed during the 3-week period after each dosage increase.	PRL Changes Mean changes in PRL levels were greater in females than in males for INVEGA SUSTENNA (37.7 ng/mL vs 9.8 ng/mL) and RLAI (31.1 ng/mL vs 8.2 ng/mL). PRL-Related TEAEs INVEGA SUSTENNA: 8.3%; RLAI: 9.0% Most common event was increase in blood PRL levels (>5%).
Open-Label Studies (≥6 Months)
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 OAPs (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 IM or gluteal IM).	Mean duration of exposure: 382.6 days; Mean maintenance dose after day 8: 157.2 mg PRL-Related TEAEs occurred in 11.9% (n=62) of patients and occurred more frequently in females than males (25.6% vs. 4.7%, respectively). Most common potential PRL-related TEAEs (≥2%): Females: amenorrhea (11.1%); menstrual disorder (5.6%); increased blood PRL (4.4%) Males: sexual dysfunction (2.1%)
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.³⁰^,³¹ Dosing Regimens: Transition from OAPs After tapering off OAPs 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 LAIs, 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 OAPs (n=212)³⁰ Potentially PRL-related TEAEs occurred in 5.7% of the total patient population; reported as: amenorrhoea (2.4%), amenorrhoea, galactorrhea (0.5%), erectile dysfunction (1.4%), galactorrhea (0.5%), gynecomastia (0.5%) and sexual dysfunction (1.4%). Nonacute Schizophrenia switched from OAPs (n=593)³¹ While protocol-based laboratory tests were not conducted during the study, 18 patients (3.0%) reported at least one potentially PRL-related TEAE, 4 patients (0.7%) reported hyperprolactinemia and 7 patients (1.2%) reported a potentially PRL-related TEAE as well as hyperprolactinemia.
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 (N=201; n=184, safety analysis set). Dosing: Deltoid IM injection on day 1 (234 mg) and day 8 (156 mg) followed by flexible once-monthly injections (deltoid IM or gluteal IM).	Patients received a mean INVEGA SUSTENNA dose of 166.8 mg for a mean duration of 238.7 days. PRL-Related TEAEs occurred in 32.8% of patients, occurring more frequently in females (41%) vs males (25%), and primarily increased blood PRL (29.9%), No patient required discontinuation of therapy. Additional potentially PRL-related TEAEs: menstrual irregularity (2.0%); amenorrhea (1.5%); galactorrhea (1.5%)
Coppola et al (2012)¹¹ 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 (Group 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 muscle) starting on day 36. Patients who were unable to tolerate the 234-mg dose or unwilling to participate in intensive pharmacokinetic sampling (Group B, n=26) received a second IM injection 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 muscle).	PRL-Related AEs Potentially PRL-related AEs occurred in 19% of patients (n=41). Incidences were higher in females (32.8%) than in males (14.3%). Majority of events were laboratory abnormalities without reported symptoms. Potentially PRL-related AEs with clinical signs and symptoms which occurred in more than one patient were libido decreased (n=4), erectile dysfunction (n=2), and amenorrhea (n=2). Three patients discontinued treatment because of PRL-related AEs. Treatment-emergent abnormal PRL levels were reported in 78% of patients.
Pooled Analysis
Einarson et al (2012)¹ pooled analysis of 10 short- and long-term clinical trials⁵^,⁸^-¹⁰^,¹²^-¹⁷^,³³ (included randomized, DB, OL, and cross-over studies; and PBO- and active-controlled studies) of INVEGA SUSTENNA (N=3173; males, 61.4%) to evaluate the frequency of symptomatic, potentially PRL-related AEs. Serum PRL levels at baseline and ≥1 post-baseline assessment were available for 89% of patients (n=2831). Doses of INVEGA SUSTENNA ranged from 39 to 234 mg, including flexible-dose trials (weighted average dose in trials with flexible dosing was 108.5 mg monthly). INVEGA SUSTENNA vs PBO, 5 studies⁵^,⁸^,¹⁰^,¹²^,¹³^,¹⁶ INVEGA SUSTENNA vs RLAI, 3 studies⁹^,¹⁴^,¹⁷ Cross-over comparison of INVEGA SUSTENNA between gluteal and deltoid injection, 1 study¹⁵ Long-term, OL, safety study³³	Elevated PRL Levels In the INVEGA SUSTENNA group, 38.8% of patients had elevated PRL levels, with no difference between males and females (incidence was similar to that in the RLAI group, 35.4%). Hyperprolactinemia did not correlate with monthly dose of INVEGA SUSTENNA (P=0.109). PRL-Related TEAEs In the INVEGA SUSTENNA group, 3.4% of patients experienced potentially PRL-related AEs (significantly higher than in the PBO group, 1.1%; P=0.002); 44% of these AEs were associated with abnormal laboratory values, most of which were asymptomatic. Incidence of potentially PRL-related AEs that were symptomatic was 2% (exposed patients), and only 0.4% of patients required treatment. Higher INVEGA SUSTENNA doses were significantly correlated with potentially PRL-related AEs (P=0.004).
SCHIZOAFFECTIVE DISORDER
Fu et al (2013 and 2015)⁶^,³⁴ conducted an international, long-term, DB, PBO-controlled, randomized-withdrawal study of INVEGA SUSTENNA in patients with schizoaffective disorder. During the 15-month, DB phase, stable patients were randomized to PBO (n=170) or a fixed dose of INVEGA SUSTENNA (n=164) INVEGA SUSTENNA dose distribution during DB phase: 78 mg (4.9%), 117 mg (9.8%), 156 mg (47%) or 234 mg (38.4%) doses.	During the DB phase, PRL-related TEAEs occurred in 13.9% of females and 7.1% of males receiving INVEGA SUSTENNA and 5.8% of females and 1.2% of males receiving PBO. Most common (INVEGA SUSTENNA vs PBO, respectively): Females: hyperprolactinemia/blood PRL increase (8.9% vs 3.5%); amenorrhea (3.8% vs 2.3%); galactorrhea (3.8% vs 1.2%) Males: hyperprolactinemia/blood PRL increase (4.7% vs 0%)
Abbreviations: AE, adverse event; CI, confidence interval; CLOZ, clozapine; DB, double-blind; EMB, event monitoring board; HAL, haloperidol; IM, intramuscular; Inj, injection; ITT, intent-to-treat; LAI, long-acting injectable; OAP, oral antipsychotic; OL, open-label; OLA, olanzapine; OLE, open-label extension; PBO, placebo; PP3M, paliperidone palmitate 3-month; PRIDE, Paliperidone Palmitate Research In Demonstrating Effectiveness; PRL, prolactin; RIS, risperidone; RLAI, risperidone long-acting injection; SI, International System of Units; TEAE, treatment-emergent adverse event; ULN, upper limit of normal; US United States.

Real-world Observational Studies

Tost et al (2024)¹⁹ conducted a single-center, prospective, pragmatic observational study in Spain to evaluate the impact on sexual function and PRL levels in patients with schizophrenia after switching from risperidone LAI to INVEGA SUSTENNA. Sexual functioning was measured using the Arizona Sexual Experience Scale (ASEX; a 5-item scale that obtains a total score between 5 and 30, with high scores indicating sexual dysfunction). Plasma PRL and sex hormone levels were determined by immunoassays. Clinical assessments and laboratory measurements were taken at baseline, 3, and 6 months post-switch.

The analysis included 27 patients (mean age, 35 years; male, 81.5%), with a mean (standard deviation) disease duration of 8.9 (2.1) months and age of disease onset at 26.1 years. Men were younger than women (33.1 years vs 43.8 years), with no significant difference in baseline antipsychotic doses. At 6 months post-switch, PRL levels in women significantly decreased from the baseline (119.9 ± 65.5 to 83.0 ± 40.7 ng/ml; P<0.001), with no significant changes in men over the same period. Additionally, higher antipsychotic doses (measured in risperidone equivalents) were associated with higher PRL levels (P=0.006). No significant differences in ASEX total scores were observed 6 months post-switch, and clinical sexual dysfunction rates decreased from 51.9% at baseline to 37.0% at 3 months and 36.4% at 6 months, but this change was not statistically significant (P=0.125).

Pappa et al (2023)²⁰ conducted a real-world, 10-year, mirror-image, observational study between 2011 and 2021 in the United Kingdom to evaluate the long-term effect of INVEGA SUSTENNA on hospitalization rate and treatment discontinuation.

Of 167 patients who were initiated on INVEGA SUSTENNA, 70% (n=117) were primarily diagnosed with schizophrenia and the remaining 30% (n=50) with schizoaffective disorder, bipolar affective disorder, or other diagnoses. Overall, the continuation rates of INVEGA SUSTENNA in the first, second, third, fourth, and fifth years were 76%, 64.7%, 53.3%, 50.3%, and 46.1%, respectively, in the total cohort. Treatment with INVEGA SUSTENNA was discontinued due to poor tolerability, ineffectiveness, or poor adherence. Of the 33 patients who discontinued treatment due to poor tolerability, 9% (n=3) were due to hyperprolactinemia.

Case Reports

There currently are no systematically collected data to support the use of INVEGA SUSTENNA concomitantly with another antipsychotic; however, case reports examining the effects of aripiprazole on paliperidone- and INVEGA SUSTENNA-induced hyperprolactinemia have been identified.

A 25-year-old female patient, hospitalized for schizoaffective disorder, developed hyperprolactinemia (PRL level: 94 ng/mL) and amenorrhea following treatment with quetiapine 600 mg/day plus paliperidone 12 mg/day. Treatment was switched to INVEGA SUSTENNA (initiation: 234 mg day 1, 156 mg day 8 [both in the deltoid muscle]; maintenance: 156 mg monthly). Following the first two injections of INVEGA SUSTENNA, PRL levels increased to 125 ng/mL with continued amenorrhea. At discharge, 30 days after INVEGA SUSTENNA initiation, amenorrhea continued (PRL level: 105 ng/mL). Two months following discharge, the patient continued to experience amenorrhea. PRL levels remained elevated at 74 ng/mL. Aripiprazole 5 mg/day was added to her treatment. One month later, the patient's PRL level decreased to 38 ng/mL. One month after the decrease in PRL levels, amenorrhea resolved. Following 6 months of treatment with INVEGA SUSTENNA plus aripiprazole, PRL levels remained within normal limits at 31 ng/mL.³⁵
A 30-year-old female patient diagnosed with paranoid schizophrenia experienced amenorrhea and hyperprolactinemia (141 ng/mL; reference: 3-30 ng/mL) following treatment with paliperidone 12 mg/day and lorazepam 3 mg/day. Paliperidone was decreased to 9 mg/day but the patient experienced an exacerbation of positive symptoms. Paliperidone was then increased to 12 mg/day and combined with aripiprazole 5 mg/day. Four weeks later, the PRL level dropped to 37 ng/mL.³⁶
A 38-year-old patient with paranoid schizophrenia was resistant to treatment with several typical and atypical antipsychotics. During a course of risperidone (4 mg/day) and clomipramine (225 mg/day) she experienced menstrual irregularities and a PRL level of 307 ng/mL. Risperidone was switched to paliperidone 9 mg/day; however, the patient’s PRL levels still fluctuated between 228-289 ng/mL. Aripiprazole 15 mg/day was added to the patient’s treatment regimen. One month later PRL levels dropped from 253 ng/mL to 47.1 ng/mL.³⁷

Recent review articles discussing the effects of antipsychotics on serum PRL levels³⁸^,³⁹ and the clinical management of antipsychotic-induced hyperprolactinemia²¹^,⁴⁰^,⁴¹ have been referenced for your convenience.

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 October 2024.

References

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