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 5HT_2A receptors. 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. Long-standing hyperprolactinemia when 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 TRINZA, elevations of PRL to above the reference range (>13.13 ng/mL in males and >26.72 ng/mL in females) were noted in a higher percentage of INVEGA TRINZA subjects compared with placebo (PBO) (46% vs. 25% of males, and 32% vs. 15% of females, respectively).⁵
• During the double-blind (DB) phase of the long-term relapse prevention trial, potentially PRL-related treatment-emergent adverse events (TEAEs; amenorrhea) occurred in 1 of 42 female patients in the INVEGA TRINZA group. No PRL-related adverse events (AEs) were reported in the PBO group.²
• During the open-label (OL) phases, 27% of females and 42% of males experienced elevations of PRL above the reference range relative to baseline. A higher proportion of females experienced potentially PRL-related adverse reactions compared to males (7.9% vs. 3.7%). Amenorrhea (4.7%) and galactorrhea (3.1%) were the most commonly observed (≥3%) potentially PRL-related adverse reactions in females. Among males in the OL phase, no potentially PRL-related adverse reaction was observed with a rate greater than 3%.⁵
• PRL levels were also evaluated in a noninferiority trial comparing INVEGA TRINZA to INVEGA SUSTENNA.⁶ The overall incidence of PRL-related treatmentemergent adverse events was comparable between the INVEGA TRINZA and INVEGA SUSTENNA groups.
• PRL level-related adverse effects following treatment with INVEGA TRINZA have been reported in observational and real-world studies.
  • A prospective observational study of 22 adults transitioning from INVEGA SUSTENNA to INVEGA TRINZA reported increased PRL levels, without symptoms, in 9% of the patients and sexual dysfunction in 4%.⁷
  • In preliminary results from an ongoing observational study evaluating PRL levels, clinical symptomology, and sexual function in patients with schizophrenia after switching to INVEGA TRINZA from INVEGA SUSTENNA, PRL levels with INVEGA TRINZA were significantly lower in both women and men (P=0.002 and P=0.033, respectively).⁸
  • A long-term follow-up analysis of a retrospective, observational study evaluating INVEGA TRINZA monotherapy in patients with schizophrenia reported that 3 out of 97 patients discontinued due to hyperprolactinemia.⁹
  • A real-world, retrospective study examining data from the EUDRAVigilance database reported “endocrine disorders” and “reproductive system and breast disorders” as adverse drug reactions (ADRs) in the individual case safety reports (ICSRs) for INVEGA TRINZA.¹⁰

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. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq. of paliperidone, respectively.
• INVEGA TRINZA doses expressed as 273, 410, 546, and 819 mg of paliperidone palmitate are equal to 175, 263, 350, and 525 mg eq. of paliperidone, respectively.

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.^11,12

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 antipsychotics¹¹

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.^11,12,13

Two separate algorithms, specific to male and female patients for the management of hyperprolactinemia, are also described in the publication.¹¹

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.¹¹

SCHIZOPHRENIA CLINICAL STUDIES

Berwaerts et al (2015)^2,5,14 conducted a DB, PBO-controlled, relapse-prevention study to evaluate the efficacy and safety of INVEGA TRINZA in delaying time-to-relapse of schizophrenia symptoms in patients previously treated with INVEGA SUSTENNA for at least 4 months.

Study Design/Methods

• The study included 4 phases: a screening and oral tolerability testing phase of up to 3 weeks, a 17-week OL transition phase, a 12-week OL maintenance phase, and a DB phase of variable length.
  • During the transition phase, all patients except those who were receiving other long-acting injectable (LAI) antipsychotics or those who were receiving INVEGA SUSTENNA before entering the study received 4 months of INVEGA SUSTENNA treatment. Dosing included the following: Day 1: INVEGA SUSTENNA 234 mg (deltoid intramuscular [IM] administration); Day 8: INVEGA SUSTENNA 156 mg (deltoid IM administration); Days 36 and 64: INVEGA SUSTENNA 78, 117, 156, or 234 mg flexible doses (deltoid IM or gluteal IM administration); and Day 92: the same dose of INVEGA SUSTENNA as was administered on Day 64.
  • During the maintenance phase, patients received a single dose of INVEGA TRINZA (273, 410, 546, or 819 mg; a 3.5-fold multiple of the final INVEGA SUSTENNA dose administered on Day 92) in either the deltoid or gluteal muscle.
  • During the DB phase, stabilized patients were randomized 1:1 to receive a fixed dose of INVEGA TRINZA (the same dose as during the maintenance phase) or PBO. In addition to efficacy, safety and laboratory parameters were measured.

PRL levels and related treatment-emergent adverse events are presented in Table: PRL Levels and Related Adverse Events.

Savitz et al (2016)⁶ conducted a randomized, DB, parallel-group, multicenter, noninferiority study of INVEGA TRINZA and INVEGA SUSTENNA. The primary endpoint was the percentage of patients who remained relapse-free at the end of the 48-week DB phase.

Study Design/Methods

The study consisted of 4 phases: A 3-week screening phase, a 17-week, OL stabilization phase, a 48-week DB phase, and a follow-up phase.  

The study included patients between the ages of 18-70 years with a Positive and Negative Syndrome Scale (PANSS) score between 70-120 who had worsening schizophrenia symptoms and discontinued other antipsychotics due to insufficient efficacy, safety or tolerability issues with current treatment, or those with a preference for injectable medications.

During the OL phase, 1429 patients received INVEGA SUSTENNA in the following doses:

• Day 1: 234 mg (deltoid administration)
• Day 8: 156 mg (deltoid administration)
• Weeks 5 and 9: flexible dosing between 78-234 mg (deltoid or gluteal administration). The week 13 dose was the same as week 9

Based on 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 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.

PRL levels and related treatment-emergent adverse events are presented in Table: Change in Serum Prolactin Levels (PRL) and Table: Potentially Prolactin-Related Treatment-Emergent Adverse Events During OL and DB phases (ITT [OL] Analysis Set and Safety Analysis Set).

Men in the INVEGA SUSTENNA group experienced treatment-emergent abnormally high PRL levels at a greater rate than men in the INVEGA TRINZA group (45% vs 39%; OL baseline to DB). Women in both the INVEGA SUSTENNA and INVEGA TRINZA groups experienced a similar percentage of high PRL levels (32% vs 33%; OL baseline to DB).

Observational Studies

Mauri et al (2022)⁷ conducted a prospective observational study to evaluate the maintenance of clinical efficacy and tolerability, and variation of paliperidone palmitate plasma levels during the transition from INVEGA SUSTENNA to INVEGA TRINZA.

Study Design/Methods

• Adult patients (N=22) between ages of 18-66 years with schizophrenia have been included since 2017, and the observation is ongoing.
• The clinical assessments were performed at the time of the first INVEGA SUSTENNA administration and then every 28 days up to the time of switching to INVEGA TRINZA, 28 days after the first INVEGA TRINZA administration, 2 months after the first INVEGA TRINZA administration, and then every 3 months until 9 months of the first INVEGA TRINZA administration.

The mean age of patients was 46.91 years. No AEs were reported in 63% of the patients.

Increased PRL levels were reported in 9% of the patients (without related symptoms), and sexual dysfunction was reported in 4% patients. Hyperprolactinemia was dose-dependent and higher in women.

Karslioğlu et al (2022)⁸ reported preliminary findings from an ongoing, prospective, longitudinal, observational study. The study compared PRL levels, clinical symptomatology, and sexual function in patients with schizophrenia after switching to INVEGA TRINZA from INVEGA SUSTENNA.

Study Design/Methods

• Patients (N=25) with schizophrenia aged 18-65 years were included in the study.
• The first assessment (V0) was conducted during the last INVEGA SUSTENNA injection before switching to INVEGA TRINZA treatment. The second assessment (V1) was conducted during the second planned INVEGA TRINZA injection, on the 90th day (±15 days), as recommended.
• PANSS and Arizona Sexual Experiences Scale (ASEX) were used to assess the clinical symptomatology and sexual function, respectively. On the mornings of assessment, blood samples were drawn to determine the prolactin levels.  

The mean (SD) age of patients was 44.9 (11.7) years, and 52.0% (n=13) of patients were male. The PRL levels of patients after the treatment were significantly lower compared with PRL levels before the treatment (P<0.001). The mean (SD) PRL levels at V0 vs V1 were 78.8 (48.0) ng/mL vs 47.2 (29.4) ng/mL (P=0.002) in females and 31.6 (15.8) ng/mL vs 25.6 (12.3) ng/mL (P=0.033) in males.

The total score and arousal subscore of ASEX decreased significantly (P=0.015 and P=0.020, respectively). The total score and positive subscale of the PANSS decreased significantly (P=0.017 and P=0.021, respectively), at V1 compared to V0.

Hyperprolactinemia was reported by 84% of patients at V0 and 76.0% of patients at V1, and sexual dysfunction was reported by 64.0% of patients at V0 and 48% of patients at V1; however, no statistical significance was observed. A statistically significant correlation was observed between the ASEX arousal subscale score and difference in PRL levels at V1 compared with V0 (r=0.52; P<0.05). No statistically significant correlation was found between the PANSS score, other ASEX subscale scores, and the difference in PRL levels.

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

• Five patients (5%) relapsed, all within the first 18 months of the observation period.
• Out of 33 (34.0%) patients who discontinued INVEGA TRINZA, 8 (24.2%) were due to adverse effects, including 3 due to hyperprolactinemia.

Real-world Retrospective Study

Cicala et al (2023)¹⁰ conducted a real-world, retrospective study analyzing ICSR data from the EUDRAVigilance database between 2011 and 2022 for the use of INVEGA SUSTENNA and INVEGA TRINZA.

A total of 8,152 ICSRs for INVEGA SUSTENNA and INVEGA TRINZA were reported for the 20,226 second-generation antipsychotic LAI cases examined. The frequency of “endocrine disorders” and “reproductive system and breast disorders” reported as ADRs in the ICSRs for INVEGA TRINZA were 2% (n/N=34/1,731) and 6% (n/N=104/1,731), respectively.

CASE REPORTS

There currently are no systematically collected data to support the use of INVEGA TRINZA concomitantly with another antipsychotic; however, case reports examining the effects of aripiprazole on paliperidone- and paliperidone palmitate-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 paliperidone palmitate, 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.¹⁵
• 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.¹⁶
• 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.¹⁷

LITERATURE SEARCH

A literature search of Ovid MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENTDrug Files databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 16 September 2024.