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 phase 3, 12-month, randomized, double-blind (DB), active-controlled, parallel-group, noninferiority trial conducted to evaluate the efficacy and safety of INVEGA HAFYERA (N=478) relative to INVEGA TRINZA (N=224), median PRL levels remained relatively stable throughout the open-label (OL) and DB phases in males.⁵
  • In females, median PRL levels increased from OL baseline to DB baseline and continued to increase after dosing in both the INVEGA HAFYERA and INVEGA TRINZA groups during DB treatment, returning to DB baseline levels at Month 12 (end of DB phase).⁶
  • PRL-related treatment-emergent adverse events (TEAEs) occurred in a similar percentage of patients in the INVEGA HAFYERA (3.8%) and INVEGA TRINZA (3.1%) groups during the DB phase. There was no correlation between PRL levels and potentially PRL-related TEAEs.⁶
• In a 2-year, single-arm, open-label extension (OLE) of the phase 3, DB, noninferiority study, increased PRL/hyperprolactinemia was reported in 32 (18%) patients on INVEGA HAFYERA.⁷

DOSAGE STRENGTH INFORMATION

Doses of paliperidone palmitate can be expressed in mg eq. of paliperidone (active moiety) or mg of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq. of paliperidone, respectively.
• INVEGA TRINZA doses expressed as 273, 410, 546, and 819 mg of paliperidone palmitate are equal to 175, 263, 350, and 525 mg eq. of paliperidone, respectively.
• INVEGA HAFYERA doses expressed as 1,092 or 1,560 mg of paliperidone palmitate are equal to 700 and 1,000 mg eq. of paliperidone, respectively.

BACKGROUND

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.^8,9

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.⁸

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.^8,9,10

Two separate algorithms, specific to male and female patients for the management of hyperprolactinemia, are also described in the publication.⁸

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.⁸

CLINICAL DATA

Noninferiority Trial⁵

A phase 3, randomized, DB, active-controlled, parallel-group, multicenter, noninferiority trial was conducted to evaluate the efficacy and safety of INVEGA HAFYERA relative to INVEGA TRINZA on time to first relapse in adults with schizophrenia who were previously stabilized on corresponding doses of INVEGA SUSTENNA or INVEGA TRINZA (see Figure: Study Design).

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

High PRL levels relative to reference range from maintenance baseline were noted in a similar percentage of patients in the INVEGA HAFYERA and INVEGA TRINZA groups in both males (35% and 35.7%, respectively) and females (28.9% and 30%, respectively).⁶ There was no correlation between PRL levels and potentially PRL-related TEAEs.⁶

In the DB phase, PRL-related TEAEs occurred in a similar percentage of patients (INVEGA HAFYERA: 3.8% [n=18/478]; INVEGA TRINZA: 3.1% [n=7/224]).⁶ The most frequently observed (≥1%) potentially PRL-related TEAE was amenorrhea in both the INVEGA HAFYERA (3.3%, n=5/478) and the INVEGA TRINZA (1.3%, n=3/224) groups.

None of the potentially PRL-related TEAEs were reported as a serious adverse event (SAE) during the OL phase. One report each of erectile dysfunction and irregular menstruation (0.1%) led to study drug discontinuation.⁶ None of the potentially PRL-related TEAs were reported as a serious adverse event or led to study drug discontinuation during the DB phase.

OLE Phase of the Noninferiority Study

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

In the OLE phase, increased PRL/hyperprolactinemia was reported in 32 (18%) patients on INVEGA HAFYERA, which included 9 (15.8%) patients who transitioned from INVEGA TRINZA and 23 (19.0%) patients who were on INVEGA HAFYERA during the DB phase. In women, the median PRL levels increased steadily from baseline to 12 months and decreased steadily between 12 and 24 months; the mean PRL value increased due to substantial fluctuations in individual PRL levels. In men, the median PRL levels remained stable throughout the study.

CASE REPORTS

There currently are no systematically collected data to support the use of INVEGA HAFYERA 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 PP1M (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 PP1M 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 PP1M  plus aripiprazole, PRL levels remained within normal limits at 31 ng/mL.¹²
• 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.¹³
• 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.¹⁴

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 11 June 2024.